1. Name of the medicinal product
a) Conjugated Estrogen Tablets USP 0.3mg TajPharma
b) Conjugated Estrogen Tablets USP 0.625mg TajPharma
c) Conjugated Estrogen Tablets USP 1.25mg TajPharma
2. Qualitative and quantitative composition
a)Each sugar coated tablet contains:
0.3mg of Conjugated Estrogen USP
in their naturally occurring, water soluble conjugated form.
Colour: Erythrosine, Indigocarmine, Sunset yellow FCF, Titanium dioxide
b)Each sugar coated tablet contains:
0.625mg of Conjugated Estrogen USP
in their naturally occurring, water soluble conjugated form.
Colour: Erythrosine, Indigocarmine, Sunset yellow FCF, Titanium dioxide
c)Each sugar coated tablet contains:
1.25mg of Conjugated Estrogen USP
in their naturally occurring, water soluble conjugated form.
Colour: Erythrosine, Indigocarmine, Sunset yellow FCF, Titanium dioxide
3. Pharmaceutical form
Coated Tablet. Maroon oval biconvex sugar-coated tablet
4. Clinical particulars
4.1 Therapeutic indications
− Hormone replacement therapy for estrogen deficiency symptoms in 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.
4.2 Posology and method of administration
Adults:
Conjugated estrogen is an estrogen only HRT.
Treatment of Postmenopausal Symptoms
Conjugated estrogen 0.3-1.25mg daily is the usual starting dose for women without a uterus. Continuous administration is recommended.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration
should be used. Treatment to control menopausal symptoms should be initiated with Conjugated estrogen 0.3mg. If symptoms are not adequately controlled, higher doses of Conjugated estrogen may be prescribed. Once treatment is established the lowest effective dose necessary for the relief of symptoms should be used. Patients should be re-evaluated periodically to determine if treatment for symptoms is still necessary.
Prevention of postmenopausal osteoporosis:
When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.
The minimum effective dose is 0.625mg daily for most patients.
Starting or Changing Treatment
In women who are not taking hormone replacement therapy or women who switch from a continuous combined hormone replacement therapy product, treatment may be started on any convenient day. In women transferring from a sequential hormone replacement therapy regimen, treatment should begin the day following completion of the prior regimen.
Concomitant progestogen use for women with a uterus
In women with a uterus, where the addition of a progestogen is necessary it should be added for at least 12-14 days every 28 day cycle to reduce the risk to the endometrium.
Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.
The benefits of the lower risk of endometrial hyperplasia and endometrial cancer due to adding progestogen should be weighed against the increased risk of breast cancer.
Forgotten tablet
If a tablet is forgotten, it should be taken as soon as the patient remembers, therapy should then be continued as before. If more than one tablet has been forgotten only the most recent tablet should be taken, the patient should not take double the usual dose to make up for missed tablets.
Missed pills may cause breakthrough bleeding in women with a uterus.
Elderly
There are no special dosage requirements for elderly patients, but as with all medicines, the lowest effective dose should be used.
Paediatric population
Safety and effectiveness in pediatric patients have not been established. Estrogen treatment of prepubertal girls induces premature breast development and vaginal cornification, and may induce uterine bleeding.
Since large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, hormonal therapy should not be started before epiphyseal closure has occurred in order not to compromise final growth.
Method of administration
For Oral administration
Tablets should be taken whole; do not divide, crush, chew, or dissolve tablets in mouth.
4.3 Contraindications
1. Known, suspected or history of breast cancer
2. Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer)
3. Undiagnosed genital bleeding
4. Untreated endometrial hyperplasia
5. Previous or current venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism)
6. Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency)
7. Active or recent arterial thromboembolic
disease (e.g. angina, myocardial infarction)
8. Acute liver disease or history of liver disease where the liver function tests have failed to return to normal
9. Hypersensitivity to the active substance or to any of the excipients.
10. 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 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.
1. 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 women. Women should be advised what changes in their breasts should be reported to their doctor or nurse. 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.
2. 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 supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Conjugated estrogen, in particular:
− Leiomyoma (uterine fibroids) or endometriosis
− Risk factors for thromboembolic disorders
− Risk factors for estrogen dependent tumours (e.g. first degree heredity for breast cancer)
− Hypertension
− Liver disorders (e.g. liver adenoma)
− Diabetes mellitus with or without vascular involvement
− Cholelithiasis
− Migraine or (severe) headaches
− Systemic lupus erythematosus (SLE)
− A history of endometrial hyperplasia (see below)
− Epilepsy
− Asthma
− Otosclerosis
3. Reasons for immediate withdrawal of therapy
Therapy should be discontinued if a contra-indication is discovered and in the following situations:
− Jaundice or deterioration in liver function
− Significant increase in blood pressure
− New onset of migraine-type headache
− Pregnancy
4. Endometrial Hyperplasia and Carcinoma
In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose. After stopping treatment risk may remain elevated for at least 10 years.
The addition of a progestogen for at least 12 days per month/28 day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.
For oral doses of conjugated equine estrogens >0.625 mg the endometrial safety of added progestogens has not been demonstrated. The reduction in risk to the endometrium should be weighed against the increase in the risk of breast cancer of added progestogen.
Breakthrough 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 estrogen stimulation may lead to pre-malignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis (but see above).
5. Breast Cancer
The overall evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestogen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT.
The Women’s Health Initiative trial (WHI) found no increase in the risk of breast cancer in hysterectomised women using estrogen-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 estrogen-progestogen combinations.
For all HRT, an excess risk becomes apparent within a few years of use and increases with the duration of intake but returns to baseline within a few (at most five) years after stopping treatment.
HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
6. 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 estrogen-only or combined estrogen-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.
7. Venous thromboembolism
Hormone replacement therapy (HRT) is associated with a 1.3-3 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.
Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. HRT is therefore contraindicated in these patients. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition.
Generally recognised risk factors for VTE include, use of estrogens, older age, major surgery, prolonged immobilisation, obesity (Body Mass Index >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 scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. If prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs 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 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 potential thromboembolic symptoms (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
8. 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 estrogen-progestogen or estrogen-only HRT. Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.
9. Ischaemic Stroke
Combined estrogen-progestogen and estrogen-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.
In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) compared to women receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg) versus those receiving placebo (18 versus 21 per 10,000 women-years).
Other Conditions
10. Estrogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed.
11. The use of estrogen may influence the laboratory results of certain endocrine tests and liver enzymes.
Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered.
Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).
Some patients dependent on thyroid hormone replacement therapy may require increased doses in order to maintain their free thyroid hormone levels in an acceptable range. Therefore, patients should have their thyroid function monitored more frequently when commencing concurrent treatment in order to maintain their free thyroid hormone levels in an acceptable range.
12. A worsening of glucose tolerance may occur in patients taking estrogens and therefore diabetic patients should be carefully observed while receiving hormone replacement therapy.
13. There is an increase in the risk of gallbladder disease in women receiving HRT (see Conditions that need supervision).
14. Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.
15. Estrogens should be used with caution in individuals with severe hypocalcaemia.
16. HRT use does not improve cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65.
17. Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.
18. Laboratory monitoring
Estrogen administration should be guided by clinical response rather than by hormone levels (e.g., estradiol, FSH).
19. This product contains lactose monohydrate and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine
4.5 Interaction with other medicinal products and other forms of interaction
The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 3A4 (CYP3A4) enzymes. Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, phenytoin, carbamazepine, rifampicin, rifabutin, nevirapine, efavirenz and dexamethasone , may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, nelfinavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in side effects.
Interference with Laboratory and Other Diagnostic Tests
Laboratory test interactions
Increased platelet count decreased levels of antithrombin III, and increased plasminogen antigen and activity.
Estrogens increase thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels by column or by radioimmunoassay or T3 levels by radioimmunoassay. 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., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free or biologically active hormone concentrations may be decreased.
Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels.
Impaired glucose tolerance.
The response to metyrapone may be reduced.
4.6 Fertility, pregnancy and lactation
Pregnancy
Conjugated estrogen is not indicated during pregnancy.
For women with a uterus
If pregnancy occurs during medication with Conjugated estrogen treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.
Breast-feeding
Conjugated estrogen is not indicated during lactation.
4.7 Effects on ability to drive and use machines
No studies on the effect of ability to drive or use machines have been performed
4.8 Undesirable effects
Adverse drug reactions (ADRs)
| System Organ Class | Common ADRs (>1/100, < 1/10) | Uncommon ADRs (>1/1000, <1/100) | Rare ADRs (>1/10000, <1/1000) | Very Rare ADRs (<1/10000), isolated reports |
| Infections and infestations | Vaginitis, including vaginal candidiasis | |||
| Neoplasms benign and malignant (including cysts and polyps) | Fibrocystic breast changes; Ovarian cancer; Growth potentiation of benign meningioma | Enlargement of hepatic haemangiomas | ||
| Immune system disorders | Hypersensitivity | Anaphylactic/ anaphylactoid reactions, including urticaria and angioedema | ||
| Metabolism and nutrition disorders | Glucose intolerance | Exacerbation of porphyria; Hypocalcaemia | ||
| Psychiatric disorders | Depression | Changes in libido; Mood disturbances; | Irritability | |
| Nervous system disorders | Dizziness; Headache; Migraine; Anxiety | Stroke; Exacerbation of epilepsy | Exacerbation of chorea | |
| Eye disorders | Intolerance to contact lenses | Retinal vascular thrombosis | ||
| Cardiac disorders | Myocardial infarction | |||
| Vascular disorders | Venous thrombosis; Pulmonary embolism | Superficial thrombophlebitis | ||
| Respiratory, thoracic and mediastinal disorders | Exacerbation of asthma | |||
| Gastrointestinal disorders | Nausea; Bloating; Abdominal pain | Vomiting; Pancreatitis; Ischaemic colitis | ||
| Hepatobiliary disorders | Gallbladder disease | Cholestatic jaundice | ||
| Skin and subcutaneous tissue disorders | Alopecia | Chloasma/melasma; Hirsutism; Pruritus; Rash | ||
| Musculoskeletal, connective tissue and bone disorders | Arthralgias; Leg cramps | |||
| Reproductive system & breast disorders | Abnormal uterine bleeding (Breakthrough bleeding/spotting); Breast pain, tenderness, enlargement, discharge; Leucorrhoea | Change in menstrual flow; Change in cervical ectropion and secretion | Dysmenorrhoea /pelvic pain; Galactorrhoea; Increased size of uterine leiomyomata | |
| General disorders and administration site conditions | Oedema | |||
| Investigations | Changes in weight (increase or decrease); Increased triglycerides | Increases in blood pressure |
The adverse reactions listed in the table are based on post-marketing spontaneous (reporting rate), clinical trials and class-effects.
Breast Cancer
• An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestogen therapy for more than 5 years.
• Any increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestogen combinations.
• The level of risk is dependent on the duration of use.
• 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’ use
| Age range (years) | Additional cases per 1000 never-users of HRT over a 5 year period* | Risk ratio & 95%CI# | Additional cases per 1000 HRT users over 5 years (95%CI) |
| Estrogen only HRT | |||
| 50-65 | 9-12 | 1.2 | 1-2 (0-3) |
| Combined estrogen-progestogen | |||
| 50-65 | 9-12 | 1.7 | 6 (5-7) |
| #Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately. | |||
US WHI studies – additional risk of breast cancer after 5 years’ use
| Age range (yrs) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio & 95%CI | Additional cases per 1000 HRT users over 5 years (95%CI) |
| CEE estrogen-only | |||
| 50-79 | 21 | 0.8 (0.7 – 1.0) | -4 (-6 – 0)** |
| CEE+MPA estrogen & progestogen‡ | |||
| 50-79 | 17 | 1.2 (1.0 – 1.5) | +4 (0 – 9) |
When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.
*Taken from baseline incidence rates in developed countries
**WHI study in women with no uterus, which did not show an increase in risk of breast cancer
Endometrial Cancer
Postmenopausal women with a uterus
The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.
In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer.
Depending on the duration of estrogen-only use and estrogen 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 estrogen-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 and combined estrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed
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. Results of theWHI studies are presented:
| Age range (years) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio and 95%CI | Additional cases per 1000 HRT users |
| Oral estrogen-only* | |||
| 50-59 | 7 | 1.2 (0.6-2.4) | 1 (-3 – 10) |
| Oral combined estrogen-progestogen | |||
| 50-59 | 4 | 2.3 (1.2 – 4.3) | 5 (1 – 13) |
Risk of ischaemic stroke
• The use of estrogen-only and estrogen + 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,
WHI studies combined – Additional risk of ischaemic stroke* over 5 years’ use
| Age range (years) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio and 95%CI | Additional cases per 1000 HRT users over 5 years |
| 50-59 | 8 | 1.3 (1.1 1.6) | 3 (1-5) |
*no differentiation was made between ischaemic and haemorrhagic stroke.
Other adverse reactions reported in association with estrogen/progestogen treatment including Conjugated estrogen:
• Estrogen-dependent neoplasms benign and malignant, e.g. endometrial hyperplasia, endometrial cancer.
• Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users..
• Myocardial infarction.
• Gallbladder disease.
- Skin and subcutaneous disorders: erythema multiforme, erythema nodosum, vascular purpura
• Probable dementia over the age of 65.
• Exacerbation of otosclerosis.
• Gynecomastia in males.
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.
Overdose
Symptoms of overdosage of estrogen-containing products in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/ fatigue and withdrawal bleeding may occur in females. There is no specific antidote, and further treatment should be symptomatic.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Conjugated Estrogens
The active ingredients are primarily the sulfate esters of estrone, equilin sulfates, 17α-estradiol and 17β-estradiol. These substitute for the loss of estrogen production in menopausal women, and alleviate menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.
Mechanism of Action
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.
Effects on estrogen-deficiency (vasomotor) symptoms
In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2,805 postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight treatment groups, receiving either placebo or conjugated estrogens, with or without medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first 12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least seven moderate-to-severe hot flushes daily, or at least 50
moderate-to-severe hot flushes during the week before randomization. With conjugated estrogen (0.3 mg, 0.45 mg, and 0.625 mg tablets), the decrease of both the frequency and severity of moderate-to-severe vasomotor symptoms was shown to be statistically improved compared with placebo at weeks 4 and 12.
Table 1 shows the observed mean number of hot flushes in the CE 0.3 mg, 0.45 mg, and 0.625 mg and placebo treatment groups over the initial 12-week period.
Standard errors based on assumption of equal variances.
| TABLE 1. SUMMARY TABULATION OF THE NUMBER OF HOT FLUSHES PER DAY– MEAN VALUES AND COMPARISONS BETWEEN THE CE TREATMENT GROUPS AND THE PLACEBO GROUP: PATIENTS WITH AT LEAST 7 MODERATE TO SEVERE FLUSHES PER DAY OR AT LEAST 50 PER WEEK AT BASELINE, EFFICACY EVALUABLE (EE) POPULATION | ||||
| Treatment (No. of Patients) | ————— No. of Hot Flushes/Day —————— | |||
| Time Period (week) | Baseline Mean ± SD | Observed Mean ± SD | Mean Change ± SEa | p-Values vs. Placeboa |
| 0.625 mg CE | ||||
| 4 (n=27) | 12.29 ± 3.89 | 1.95 ± 2.77 | -10.34 ± 0.90 | <0.001 |
| 12 (n=26) | 12.03 ± 3.73 | 0.45 ± 0.95 | -11.58 ± 0.88 | <0.001 |
| 0.45 mg CE | ||||
| 4 (n=32) | 12.25 ± 5.04 | 5.04 ± 5.31 | -7.21 ± 0.83 | <0.001 |
| 12 (n=30) | 12.49 ± 5.11 | 2.33 ± 3.39 | -10.16 ± 0.82 | <0.001 |
| 0.3 mg CE | ||||
| 4 (n=30) | 13.77 ± 4.78 | 4.65 ± 3.71 | -9.12 ± 0.85 | <0.001 |
| 12 (n=29) | 13.83 ± 4.86 | 2.20 ± 2.73 | -11.63 ± 0.83 | <0.001 |
| Placebo | ||||
| 4 (n=28) | 11.69 ± 3.87 | 7.89 ± 5.28 | -3.80 ± 0.88 | – |
| 12 (n=25) | 11.61 ± 3.79 | 5.27 ± 4.97 | -6.34 ± 0.89 | – |
Prevention of osteoporosis
| TABLE 2. PERCENT CHANGE IN BONE MINERAL DENSITY: COMPARISON BETWEEN CE AND PLACEBO GROUPS IN THE INTENT-TO-TREAT POPULATION, LOCF. | ||||
| Region Evaluated Treatment Groupa | No. of Subjects | Baseline (g/cm2) Mean ± SD | Change from Baseline (%) Adjusted Mean ± SE | p-Value vs Placebo |
| L2 to L4 BMD | ||||
| 0.625 | 83 | 1.17 ± 0.15 | 2.32 ± 0.35 | <0.001 |
| 0.45 | 91 | 1.13 ± 0.15 | 2.08 ± 0.34 | <0.001 |
| 0.3 | 87 | 1.14 ± 0.15 | 1.24 ± 0.34 | <0.001 |
| Placebo | 85 | 1.14 ± 0.14 | -2.46 ± 0.35 | |
| Total body BMD | ||||
| 0.625 | 84 | 1.15 ± 0.08 | 0.66 ± 0.17 | <0.001 |
| 0.45 | 91 | 1.14 ± 0.08 | 0.71 ± 0.16 | <0.001 |
| 0.3 | 87 | 1.14 ± 0.07 | 0.37 ± 0.16 | <0.001 |
| Placebo | 85 | 1.13 ± 0.08 | -1.52 ± 0.16 | |
| Femoral neck BMD | ||||
| 0.625 | 84 | 0.91 ± 0.14 | 1.74 ± 0.43 | <0.001 |
| 0.45 | 91 | 0.89 ± 0.13 | 1.95 ± 0.41 | <0.001 |
| 0.3 | 87 | 0.86 ± 0.11 | 0.57 ± 0.42 | <0.001 |
| Placebo | 85 | 0.88 ± 0.14 | -1.81 ± 0.43 | |
| Femoral trochanter BMD | ||||
| 0.625 | 84 | 0.78 ± 0.13 | 3.78 ± 0.57 | <0.001 |
| 0.45 | 91 | 0.76 ± 0.12 | 3.46 ± 0.54 | <0.001 |
| 0.3 | 87 | 0.75 ± 0.10 | 3.19 ± 0.55 | 0.003 |
| Placebo | 85 | 0.75 ± 0.12 | 0.93 ± 0.56 | |
At present there is no established screening programme for determining women at risk of developing osteoporotic fracture. Epidemiological studies suggest a number of individual risk factors which contribute to the development of postmenopausal osteoporosis. These include: early menopause; family history of osteoporosis; thin, small frame; cigarette use; recent prolonged systemic corticosteroid use.
Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.
Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestogen – given to predominantly healthy women – reduces the risk of hip, vertebral and other osteoporotic fractures. HRT may also help prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.
Effect on bone mineral density
Health and Osteoporosis, Progestin and Estrogen (HOPE) Study
The HOPE study was a double-blind, randomized, placebo/active-drug-controlled, multicenter study of healthy postmenopausal women with an intact uterus. Subjects (mean age 53.3 ± 4.9 years) were 2.3 ± 0.9 years on average since menopause and took one 600 mg tablet of elemental calcium (Caltrate™) daily. Subjects were not given Vitamin D supplements. They were treated with conjugated estrogen 0.625 mg, 0.45 mg, 0.3 mg, or placebo. Prevention of bone loss was assessed by measurement of bone mineral density (BMD), primarily at the anteroposterior lumbar spine (L2 to L4). Secondarily, BMD measurements of the total body, femoral neck, and trochanter were also analyzed. Serum osteocalcin, urinary calcium, and N telopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and 26.
Intent-to-treat subjects
All active treatment groups showed significant differences from placebo in each of the four BMD endpoints at cycles 6, 13, 19, and 26. The percent changes from baseline to final evaluation are shown in Table 2.
The bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased (p < 0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo group. Larger mean decreases from baseline were seen with the active groups than with the placebo group. Significant differences from placebo were seen less frequently in urine calcium.
WHI Estrogen-Alone Substudy
Timing of the initiation of estrogen therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50-59 years of age, a non-significant trend towards reduced risk for CHD and overall mortality compared with placebo in women who initiated hormone therapy closer to menopause than those initiating therapy more distant from menopause.
Table 3 describes the primary results of the Estrogen-alone substudy stratified by age at baseline.
| TABLE 3. WOMEN’S HEALTH INITIATIVE ESTROGEN-ALONE SUBSTUDY RESULTS STRATIFIED BY AGE AT BASELINE | ||||||
| AGE | ||||||
| Endpoint | 50-59 years | 60-69 years | 70-79 years | |||
| CE(N=1637) | Placebo(N=1673) | CE(N=2387) | Placebo(N=2465) | CE(N=1286) | Placebo(N=1291) | |
| CHDa,b | ||||||
| Number of cases | 21 | 34 | 96 | 106 | 84 | 77 |
| Absolute risk (N) c | 17 | 27 | 58 | 62 | 98 | 88 |
| Hazard ratio(95% CI) | 0.63 (0.36-1.09) | 0.94 (0.71-1.24) | 1.13 (0.82-1.54) | |||
| Strokeb | ||||||
| Number of cases | 18 | 21 | 84 | 54 | 66 | 52 |
| Absolute risk (N)c | 15 | 17 | 51 | 31 | 76 | 59 |
| Hazard ratio(95% CI) | 0.89 (0.47-1.69) | 1.62 (1.15-2.27) | 1.21 (0.84-1.75) | |||
| DVTb | ||||||
| Number of cases | 16 | 10 | 39 | 29 | 30 | 20 |
| Absolute risk (N)c | 13 | 8 | 23 | 17 | 34 | 22 |
| Hazard ratiod(95% CI) | 1.64 (0.74-3.60) | 3.02 (1.51-6.06) | 4.54 (2.22-9.31) | |||
| VTE b [16] | ||||||
| Number of cases | 20 | 15 | 54 | 43 | 37 | 28 |
| Absolute risk (N)c | 16 | 12 | 32 | 25 | 42 | 31 |
| Hazard ratio d(95% CI) | 1.37 (0.70-2.68) | 2.82 (1.59-5.01) | 3.77 (2.07-6.89) | |||
| Pulmonary Embolism b | ||||||
| Number of cases | 12 | 8 | 28 | 17 | 12 | 14 |
| Absolute risk (N)c | 10 | 6 | 17 | 10 | 14 | 16 |
| Hazard ratiod(95% CI) | 1.54 (0.63-3.77) | 2.80 (1.28-6.16) | 2.36 (0.96-5.80) | |||
| Invasive Breast Cancer | ||||||
| Number of cases | 25 | 35 | 42 | 60 | 27 | 29 |
| Absolute risk (N)c | 21 | 29 | 26 | 36 | 32 | 34 |
| Hazard ratio(95% CI) | 0.72 (0.43-1.21) | 0.72 (0.49-1.07) | 0.94 (0.56-1.60) | |||
| Colorectal Cancer | ||||||
| Number of cases | 8 | 14 | 26 | 31 | 27 | 13 |
| Absolute risk (N)c | 7 | 12 | 16 | 19 | 32 | 15 |
| Hazard ratio(95% CI) | 0.59 (0.25-1.41) | 0.88 (0.52-1.48) | 2.09 (1.08-4.04) | |||
| Hip Fractureb | ||||||
| Number of cases | 5 | 1 | 9 | 20 | 32 | 52 |
| Absolute risk (N)c | 4 | 1 | 5 | 12 | 37 | 58 |
| Hazard ratio(95% CI) | 5.02 (0.59-43.02) | 0.47 (0.22-1.04) | 0.64 (0.41-0.99) | |||
| Total Fracturesb | ||||||
| Number of cases | 153 | 173 | 220 | 348 | 167 | 240 |
| Absolute risk (N)c | 126 | 139 | 132 | 201 | 191 | 269 |
| Hazard ratio(95% CI) | 0.90 (0.72-1.12) | 0.63 (0.53-0.75) | 0.70 (0.57-0.85) | |||
| Overall Mortalityb | ||||||
| Number of cases | 34 | 48 | 129 | 131 | 134 | 113 |
| Absolute risk (N)c | 28 | 38 | 77 | 75 | 153 | 127 |
| Hazard ratio(95% CI) | 0.71 (0.46-1.11) | 1.02 (0.80-1.30) | 1.20 (0.93-1.55) | |||
a CHD defined as myocardial infarction or coronary death
a Based on adjudicated data over a mean duration of therapy of 7.1 years
- Absolute risk is per 10,000 person-years.
- VTE hazard ratios compared with women aged 50-59 taking placebo
5.2 Pharmacokinetic properties
Absorption
Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. Conjugated estrogen tablets release conjugated estrogens slowly over several hours. Maximum plasma concentrations are achieved approximately 6-10 hours following administration. The estrogens are generally eliminated in near-parallel fashion, with half-lives ranging from 10-20 hours, when corrected for endogenous concentrations as needed.
The pharmacodynamic profile of unconjugated and conjugated estrogens following a dose of 2 x 0.625mg is provided in Table 1.
Table 1 – Pharmacokinetic parameters for Conjugated estrogen
| Conjugated estrogen 0.625mg | ||||
| Drug PK Parameter Arithmetic Mean (%CV) | Cmax (pg/mL) | tmax (h) | t1/2 (h) | AUC (pg.h/mL)* |
| estrone | 139 (37) | 8.8 (20) | 28.0 (13) | 5016 (34) |
| baseline-adjusted estrone | 120 (42) | 8.8 (20) | 17.4 (37) | 2956 (39) |
| equilin | 66 (42) | 7.9 (19) | 13.6 (52) | 1210 (37) |
Pharmacokinetic profile for unconjugated estrogens following a 2 x 0.625mg
| Conjugated estrogen 0.625mg | ||||
| Drug PK Parameter Arithmetic Mean (%CV) | Cmax (ng/mL) | tmax (h) | t1/2 (h) | AUC (pg.h/mL)* |
| total estrone | 7.3 (41) | 7.3 (51) | 15.0 (25) | 134 (42) |
| baseline-adjusted total estrone | 7.1 (41) | 7.3 (25) | 13.6 (27) | 122 (39) |
| total equilin | 5.0 (42) | 6.2 (26) | 10.1 (27) | 65 (45) |
Pharmacokinetic profile for conjugated estrogens following a dose of 2 x 0.625mg
* t1/2 = terminal-phase disposition half-life (0.693/γ)
Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.
Biotransformation
Exogenous estrogens are metabolised in the same manner as endogenous estrogens. Circulating estrogens exist in dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut following reabsorption. In post-menopausal women a significant proportion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Elimination
Estriol, estrone and estradiol are excreted in the urine along with glucuronide and sulfate conjugates.
Special Populations
No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
5.3 Preclinical safety data
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinoma of the breast, cervix, vagina and liver.
6. Pharmaceutical particulars
6.1 List of excipients
Compressed Tablet Cores:
Lactose Monohydrate (Spray Dried)
Microcrystalline Cellulose
Hypromellose 2208, K100M (100,000 cps)
Magnesium Stearate
Tablet Coating:
Filler Coat
Sucrose
Microcrystalline Cellulose
Hydroxypropyl Cellulose
Hypromellose, 2910, E6 (6 cps)
Hypromellose, 2910, E15 (15 cps)
Polyethylene Glycol 400
Colour Coat
Opadry® Maroon 03B16083#
Polishing
Hypromellose, 2910, E6 (6 cps)
Carnauba Wax
Brand
Opacode® WB NS-78-18011, White Ink##
# The colorant Opadry® Maroon 03B16083 contains: HPMC 2910/ Hypromellose, 6 cP, Titanium Dioxide, FD&C Red # 40 Aluminium Lake (E129), PEG 400/ Macrogol and FD&C Blue #2 Aluminium Lake (E132).
## The white branding ink Opacode® WB NS-78-18011 contains: Titanium Dioxide, Propylene Glycol and Hypromellose 2910, 3 cP.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
Blister pack consisting of a PVC/Aclar®/PVC and a hard tempered aluminium foil lid containing 28 tablets.
One carton pack contains 3 blisters.
Securitainers containing 100 tablets. PVC/Aluminium foil blisters containing 21 tablets.
6.6 Special precautions for disposal and other handling
No special requirements.
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
Conjugated Estrogen Tablets USP 1.25mg TajPharma
Package leaflet: Information for the patient
a) Conjugated Estrogen Tablets USP 0.3mg TajPharma
b) Conjugated Estrogen Tablets USP 0.625mg TajPharma
c) Conjugated Estrogen Tablets USP 1.25mg TajPharma
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.
What is in this leaflet
1. What Conjugated Estrogen Tablets are and what they are used for
2. What you need to know before you take Conjugated Estrogen Tablets
3. How to take Conjugated Estrogen Tablets
4. Possible side effects
5. How to store Conjugated Estrogen Tablets
6. Contents of the pack and other information
1. WHAT CONJUGATED ESTROGEN TABLETS ARE AND WHAT THEY ARE USED FOR
Conjugated Estrogen is a Hormone Replacement Therapy (HRT). It contains the female hormone estrogen. Conjugated Estrogen is used to treat some of the symptoms and conditions associated with the menopause. Conjugated Estrogen is used for:
Relief of symptoms occurring after menopause
During the menopause, the amount of the estrogen produced by a woman’s body drops. This can cause symptoms such as hot face, neck and chest (“hot flushes”). Conjugated Estrogen alleviates these symptoms after menopause. You will only be prescribed Conjugated Estrogen if your symptoms seriously hinder your daily life.
Prevention of osteoporosis
After the menopause some women may be at risk of developing fragile bones (osteoporosis). You should discuss all available treatment 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 Conjugated Estrogen 0.625 mg or 1.25 mg Coated Tablets to prevent osteoporosis after menopause. Conjugated Estrogen is usually prescribed for women who have had their womb removed (hysterectomy). However, women who have not had this operation can still take Conjugated Estrogen and their doctor may prescribe a second type of tablet containing another hormone called a progestogen to be taken for 12-14 days per month as well as the Conjugated Estrogen tablets.
2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE CONJUGATED ESTROGEN TABLETS
Medical history and regular check-up
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 Conjugated Estrogen 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 with Conjugated Estrogen.
Go for regular breast screening, as recommended by your doctor.
Do not take Conjugated Estrogen
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 Conjugated Estrogen. Do not take Conjugated Estrogen:
§If you are allergic (hypersensitive) to conjugated estrogens or any of the other ingredients of thismedicine (listed in section 6). § 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 estrogens such as cancer of the lining of the womb (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 ever had a blood clot in a vein (thrombosis), such as in the legs (deep venous 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 previously had liver disease.
§ If you have a rare blood problem called “porphyria” which is passed down in families (inherited).
§ If you are pregnant, or you are breast-feeding.
If any of the above conditions appear for the first time while taking Conjugated Estrogen, stop taking it at once and consult your doctor immediately.
Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking Conjugated Estrogen 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 Conjugated Estrogen. 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 for more detail)
· increased risk of getting estrogen-sensitive cancer (such as having a mother, sister or grandmother who has had breast cancer)
· high blood pressure
· heart disease
· a liver disorder (e.g. a benign liver tumour)
· kidney disease
· fluid retention due to cardiac or kidney problems
· diabetes
· gallbladder disease or 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)
· low blood calcium levels (hypocalcaemia)
· a very high level of fat in your blood (triglycerides).
Stop taking Conjugated Estrogen 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 Conjugated Estrogen” section
· yellowing of the 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
· have an allergic reaction, signs of which include a rash, itching, shortness of breath, difficulty in breathing and a swollen face
· if you notice signs of a blood clot, such as:
o painful swelling and redness of the legs
o sudden chest pain
o difficulty in breathing.
Conjugated Estrogen 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 estrogen-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 estrogen for at least 12 days of each 28 day cycle protects you from this extra risk. So your doctor will prescribe a progestogen separately if you still have your womb. If you have had your womb removed (a hysterectomy), discuss with your doctor whether you can safely take this product without a progestogen.
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 estrogen-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 for how long it is taken. Conjugated Estrogen 0.625 mg and 1.25 mg tablets contain a higher dose of estrogens than other estrogen-only HRT products. The risk of endometrium cancer when using Conjugated Estrogen 0.625 mg and 1.25 mg tablets together with a progestogen is not known.
If you still have your womb, your doctor may prescribe a progestogen as well as estrogen. If so, these may be prescribed separately, or as a combined HRT product.
If you have had your womb removed (a hysterectomy), your doctor will discuss with you whether you can safely take estrogen 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 estrogen.
Your product, Conjugated Estrogen, is an estrogen-only product.
Looking at women who still have a uterus 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 who take estrogen-only HRT, the number will be 2 to 12 times higher, depending on the dose and how long you take it. After stopping treatment risk may remain elevated for at least 10 years. In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer.
Irregular bleeding
If you get break-through bleeding or spotting, it’s usually nothing to worry about, especially during the first 3-6 months of taking HRT. But if the bleeding or spotting:
§ carries on for more than the first 6 months
§ starts after you’ve been taking Conjugated Estrogen for more than 6 months
§ carries on even after you’ve stopped taking Conjugated Estrogen
§ Make an appointment to see your doctor. It could be a sign that your endometrium has becomeØ thicker.
Breast Cancer
Women who have breast cancer, or have had breast cancer in the past, should not take HRT. Evidence suggests that taking combined estrogen-progestogen and possibly also estrogen-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 estrogen-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 estrogen-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 such as:
§dimpling of the skin
§ changes in the nipple
§ any lumps you can see or feel
Ovarian Cancer
Ovarian cancer is rare – much rarer than breast cancer , but it is serious. It can be difficult to diagnose, because there are often no obvious signs of the disease.
The use of estrogen-only or combined estrogen-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 your 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 in 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, collapse 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 applies to you:
§ you are seriously overweight (BMI>30 kg/m2 ) you have had a blood clot before
§ if any of your close family has ever had a blood clot in the leg, lung or another organ
§ you are pregnant or in your postpartum period
§ you have any blood clotting problem that needs treatment with a medicine used to prevent blood clots
§ you are unable to walk for a long time because of major surgery, injury or illness (see also “if you’re going to have surgery” below) §you have a rare condition called SLE (systemic lupus erythematosus)
§ you have cancer.
For signs of a blood clot, see section 2.1 Stop taking Conjugated Estrogen 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 have had their womb removed and have been taking estrogen-only HRT for over 5 years, there will be 5 to 8 cases in 1000 users (i.e. 1 extra case).
If you’re going to have surgery, make sure your doctor knows about it or tell the surgeon that you are taking Conjugated Estrogen. You may need to stop taking Conjugated Estrogen about 4 to 6 weeks before the operation, to reduce the risk of a blood clot. Your doctor will tell you when you can start taking Conjugated Estrogen again.
Heart Disease (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.
There is no evidence that HRT will prevent a heart attack.
For women who have had their womb removed and are taking estrogen-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.Ø This pain could be a sign of heart disease. Stroke
The risk of having a stroke is about 1.5 times higher in HRT users than in non-users. The number of extra cases of stroke due to use of HRT will increase with age. More recent analysis of risk in women aged 50 to 59 years suggests no increased risk for women taking 0.625 mg Conjugated Estrogen tablets.
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, over a 5-year period, 8 in 1000 would be expected to have a stroke.
For women in their 50s who are taking HRT, the figure would be 11 in 1000 users, over a five year period (i.e. an extra 3 cases).
If you get:
unexplained migraine-type headaches, with or without disturbed vision
See a doctor as soon as possible and do not take any more HRT until your doctor says you can.Ø These headaches may be an early warning sign of a stroke.
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.
Women with hypertriglyceridemia may experience large increases of their plasma triglycerides, which can lead to inflammation of the pancreas (pancreatitis). Symptoms of pancreatitis may include abdominal pain, abdominal swelling, fever and feeling or being sick.
If you are taking thyroid hormone replacement therapy (e.g. thyroxine), your doctor may monitor your thyroid function more often when you start treatment.
HRT may affect some medical tests. If you visit a hospital or clinic for any medical tests, you should tell the doctor concerned that you are taking HRT.
Other medicines and Conjugated Estrogen Some medicines may interfere with the effect of Conjugated Estrogen. This might lead to irregular bleeding. Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription, herbal remedies or other natural products.
In particular tell your doctor if you are taking: §an anticonvulsant (used to treat epilepsy e.g. phenobarbital, phenytoin, carbamazepine)
· an anti-infective e.g. used to treat tuberculosis (rifampicin, rifabutin) or HIV (nevirapine, efavirenz, ritonavir and nelfinavir) §other antibiotics or antifungal medicines (e.g. erythromycin, clarithromycin, ketoconazole, itraconazole)
§ a herbal preparation such as St. John’s wort (Hypericum perforatum)
· metyrapone (most commonly used in the treatment of Cushing’s syndrome)
· cimetidine (used to treat stomach ulcers and reduce stomach acid)
· dexamethasone (a corticosteroid)
The way that Conjugated Estrogen works may be altered if other medicines are used at the same time.
Conjugated Estrogen with food and drink Drinking grapefruit juice may affect the way that your medicine works.
Laboratory tests
If you need a blood test, tell your doctor or the laboratory staff that you are taking Conjugated Estrogen, because this medicine can affect the results of some tests.
Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
There is no evidence to suggest that taking Conjugated Estrogen will affect your ability to drive or to operate machinery.
Conjugated Estrogen contains Lactose monohydrate, Sucrose and the colouring agent Sunset Yellow Lactose monohydrate and sucrose are sugars. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product. The colouring agent E110 (sunset yellow), that is used in the yellow tablets (1.25 mg), may cause allergic reactions.
3. HOW TO TAKE CONJUGATED ESTROGEN TABLETS
Starting to take Conjugated Estrogen
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 usual dose is one tablet every day.
Your doctor will aim to give you the lowest dose for the shortest time to treat your symptoms for as short as necessary. Speak to your doctor if you think this dose is too strong or not strong enough.
Take your tablet at the same time each day as this will help to remind you to take your medicine.
If you are not already taking an HRT product or if you are taking an HRT product that does not give you a monthly bleed you may start your first pack of Conjugated Estrogen at any convenient time.
If you are changing from an HRT product that gives you a monthly bleed, start Conjugated Estrogen the day after you finish the course of the previous product, unless instructed otherwise by your doctor.
While you are taking Conjugated Estrogen you will have no tablet-free days. You should start your next pack the day after you finish the previous one.
The recommended dose
For menopausal symptoms the usual dose is one tablet every day. Your doctor will prescribe the lowest dose that will control your symptoms. Conjugated Estrogen 0.3 mg is the lowest starting dose. If your symptoms are not adequately controlled higher doses of Conjugated Estrogen can be used.
For the treatment of osteoporosis the usual dose is one 0.625 mg tablet every day but your doctor may advise you to use 1.25 mg each day. You and your doctor should review the need for treatment regularly.
Do not try to take off the coating, divide or crush the tablets as this could affect the way Conjugated Estrogen works. Paediatric population Safety and effectiveness in paediatric patients have not been established. While you are taking Conjugated Estrogen
If you have had a hysterectomy you are not expected to have a period.
If you have not had a hysterectomy, you may be taking an additional progestogen tablet for 12-14 days each month, and you will probably have a “period”, or withdrawal bleed each month at about the time you finish the additional progestogen tablets. This is caused by the hormones in the HRT and is perfectly natural. Some women taking “combined HRT” (estrogen plus the additional progestogen) may experience a gradual reduction in withdrawal bleeding and it may eventually stop; this is quite normal. If you experience troublesome bleeding or it continues beyond the first 3 months of treatment discuss this with your doctor
If you take more Conjugated Estrogen than you should
If you take too many tablets don’t worry. You may feel some nausea (sickness), breast tenderness, dizziness, abdominal pain and drowsiness/fatigue. If you have not had a hysterectomy you may experience a short period of vaginal bleeding, but it is unlikely that serious problems will occur. If you are concerned, talk to your doctor or pharmacist.
If you forget to take Conjugated Estrogen
If you forget to take a tablet don’t worry. Take it as soon as you remember and then carry on taking the remaining tablets at the usual time. Do not take a double dose to make up for a forgotten tablet.
Missed tablets may cause a short period of light bleeding in women who have not had a hysterectomy.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
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:
· 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.
In addition to those discussed in section 2, the following side effects have been reported in women taking HRT:
§ abdominal uterine bleeding such as breakthrough bleeding or spotting, changes in menstrual flow,
§ pelvic pain, vaginal inflammation and vaginal discharge a tendency to get thrush
§ breast pain, breast tenderness, swollen breasts, discharge from the nipples and changes in breast
§ tissue feeling or being sick, a feeling of being bloated, abdominal pain
§ headache or migraine
§ dizziness
§ changes in mood including anxiety, depression and irritability
§ joint pain, leg cramps
§ changes in your interest in sex (increased or decreased libido)
§ visible swelling of the face or ankles
§ rash, itchiness, acne and dark or red patches on the skin
§ changes in hair growth (loss or increase)
§ minor changes to the eye, difficulty wearing contact lenses
§ changes in weight (increase or decrease)
§ changes in your triglyceride levels (fatty substances in the blood)
§ an intolerance to glucose
§ memory loss (dementia)
§ a worsening of chorea (an existing neurological disorder characterised by involuntary spasmodic
§ movements of the body) a worsening of asthma
§ a worsening of hypocalcaemia (low blood levels of calcium)
§ gallbladder disease or jaundice (e.g. gallstones or yellowing of the skin)
§ growth of benign meningioma (a tumour of the membranes around the brain or spinal cord)
§ inflammation of the colon (part of the intestine) which may present as lower left sided abdominal
§ pain and/or bloody diarrhoea induce or exacerbate symptoms of angioedema, which consists of generalized swelling of parts of the
body, most frequently around the face, mouth, tongue and neck areas, particularly in women with hereditary angioedema.
These side effects are usually temporary and should get better over time.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below).
5. HOW TO STORE CONJUGATED ESTROGEN TABLETS
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 carton/strip after EXP. The expiry date refers to the last day of that month.
Keep the blister strips in the outer carton in order to protect from light. Do not store above 25degrees.
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. Further Information
What Conjugated Estrogen Soluble Tablets contain
The active substance is a mixture of hormones called conjugated estrogens.
Conjugated Estrogen is available in three different strengths; the green tablets marked with ‘0.3’ in white ink, the maroon tablets marked with ‘0.625’ and the yellow tablets marked with ‘1.25’.
a)Each sugar coated tablet contains:
0.3mg of Conjugated Estrogen USP
in their naturally occurring, water soluble conjugated form.
Colour: Erythrosine, Indigocarmine, Sunset yellow FCF, Titanium dioxide
b)Each sugar coated tablet contains:
0.625mg of Conjugated Estrogen USP
in their naturally occurring, water soluble conjugated form.
Colour: Erythrosine, Indigocarmine, Sunset yellow FCF, Titanium dioxide
c)Each sugar coated tablet contains:
1.25mg of Conjugated Estrogen USP
in their naturally occurring, water soluble conjugated form.
Colour: Erythrosine, Indigocarmine, Sunset yellow FCF, Titanium dioxide
The other ingredients are lactose monohydrate, microcrystalline cellulose, magnesium stearate, hypromellose, sucrose, hydroxypropyl cellulose, macrogol, carnauba wax, edible ink and coating.
What Conjugated Estrogen Tablets look like and contents of the pack
Conjugated Estrogen contains either one blister of 21 tablets or three blisters of 28 tablets in a carton or 100 tablets in a securitainer of the same colour tablets.
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
