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E-CONIK 0.625

Quick Overview

Our aim is to reach out to the globe within shortest possible time frame.  


To promote this objective, not only we distribute and market our Endocrinology  range of products globally through our distribution channels but we also undertake ‘contract manufacturing’& ‘formulation development ’of our wide range of generic products such as E-Conik .625 which contain Conjugated Estrogen USP 0.625 mg.

E-CONIK 0.625

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 E-CONIK 0.625

Each film coated tablet contains:
Conjugated Estrogen USP 0.625 mg
(in their naturally occurring water soluble conjugated form)
Excipients q.s.
Permitted colour used:
Lake Erythrosine, Lake Sunset Yellow, Lake Indigo Carmine, Titanium Dioxide 

Description:

E-CONIK 0.625: It occurs as film coated maroon color oval shaped tablet.


CLINICAL PHARMACOLOGY

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, secreted by the adrenal cortex, to estrone by 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. 


Pharmacokinetics

Absorption 
Conjugated estrogens are water-soluble and are well-absorbed from the gastrointestinal tract after release from the drug formulation. The E-CONIK tablet releases conjugated estrogens slowly over several hours. 

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 concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Metabolism 

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a 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 intestine followed by reabsorption. In postmenopausal women a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Excretion 

Estradiol, estrone and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.


INDICATIONS AND USAGE

E-CONIK therapy is indicated in the -

  • Treatment of moderate to severe vasomotor symptoms due to menopause.
  • Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.     When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
  • Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
  • Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
  • Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
  • 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 for whom non-estrogen medications are not considered to be appropriate.

The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation maybe helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women. 


DOSAGE AND ADMINISTRATION

When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (for example at 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS). For women with a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.


CONTRAINDICATIONS

E-CONIK therapy should not be used in individuals with any of the following conditions:

  • Undiagnosed abnormal genital bleeding.
  • Known, suspected, or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease.
  • Known or suspected estrogen-dependent neoplasia.
  • Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
  • Active or recent (within the past year) arterial thromboembolic disease (for example, stroke, myocardial infarction).
  • Liver dysfunction or disease.
  • Known thrombophilic disorders (e.g., protein C, protein S, or antithrombin deficiency).
  • Known hypersensitivity to any of the ingredients in E-CONIK.
  • Known or suspected pregnancy.

WARNINGS:
1. Cardiovascular disorders 

An increased risk of stroke and deep vein thrombosis (DVT) has been reported with estrogen alone therapy. 

An increased risk of stroke, DVT, pulmonary embolism and myocardial infarction has been reported with estrogen plus progestin therapy.

Should any of these events occur or be suspected, estrogens with or without progestins should be discontinued immediately.

Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (for example, personal history or family history of VTE, obesity and systemic lupus erythematosus) should be managed appropriately.

a. Stroke 
In the Women's Health Initiative (WHI) estrogen alone substudy, a statistically significant increased risk of stroke was reported in women receiving daily conjugated estrogens compared to placebo (44 versus 32 per 10,000 women-years). 

b. Coronary heart disease 
In the estrogen alone substudy of WHI, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction [MI], silent MI, or CHD death) was reported in women receiving estrogen alone compared to placebo
In postmenopausal women with documented heart disease, treatment with daily estrogen demonstrated no cardiovascular benefit

c. Venous thromboembolism (VTE) 
In the estrogen alone substudy of WHI, the risk of VTE (DVT and pulmonary embolism [PE]), was reported to be increased for women receiving daily CE compared to placebo (30 versus 22 per 10,000 women/years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women/years). The increase in VTE risk was demonstrated during the first 2 years. 
In the estrogen plus progestin substudy of WHI, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE/MPA compared to placebo (35 versus 17 per 10,000 women/years). 
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

2. Malignant neoplasms 
a. Endometrial cancer 
An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users with an intact uterus is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

b. Breast cancer 

In the estrogen alone reported substudy of WHI, after an average 7.1 years of follow-up, daily CE 0.625 mg was not associated with an increased risk of invasive breast cancer.

The results from observational studies are generally consistent with those of the WHI clinical trial. Observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.

The use of estrogen alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors and prior mammogram results.

3. Dementia 

In the estrogen alone reported substudy, after an average follow-up of 5.2 years, 28 women in the estrogen alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE alone versus placebo was 1.49 (95 percent CI 0.83-2.66). The absolute risk of probable dementia for CE alone versus placebo was 37 versus 25 cases per 10,000 women-years. 

In the estrogen plus progestin reported substudy, after an average follow-up of 4 years, 40 women in the CE/MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE/MPA versus placebo was 2.05 (95 percent CI 1.21-3.48). The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use)

4. Gallbladder Disease 

A 2 to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5. Hypercalcemia 

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

6. Visual abnormalities 

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.
7. Angioedema 
Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.

SPECIAL WARNINGS AND PRECAUTION

 

WARNINGS

ENDOMETRIAL CANCER
Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. 

CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or Cardiovascular disorders and Dementia.

IMPAIRMENT OF FERTILITY
Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.


PRECAUTIONS

A. General 
1. Addition of a progestin when a woman has not had a hysterectomy 
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include: a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (lowering HDL, raising LDL) and impairment of glucose tolerance.

2. Elevated blood pressure 

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals during estrogen use.

3. Hypertriglyceridemia 

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. Consider discontinuation of treatment if pancreatitis or other complications develop. 

4. Impaired liver function and past history of cholestatic jaundice 

Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.

5. Hypothyroidism 
Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

6. Fluid retention 

Estrogens may cause some degree of fluid retention. Patients with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

7. Hypocalcemia 

Estrogens should be used with caution in individuals with severe hypocalcemia.

8. Ovarian cancer

The estrogen plus progestin substudy of WHI reported a non-statistically significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was reported. 

In some epidemiologic studies, the use of estrogens-progestin and estrogen-only products has been associated with an increased risk of ovarian cancer over multiple years of use. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.

9. Exacerbation of endometriosis 

Endometriosis may be exacerbated with administration of estrogen therapy.

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

10. Exacerbation of other conditions 

Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus and hepatic hemangiomas and should be used with caution in patients with these conditions.

B. Patient Information

Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe E-CONIK.

C. Laboratory Tests 

Serum follicle stimulating hormone and estradiol levels have not been shown t to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy. Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure.

D. Drug/Laboratory Test Interactions 


  • Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and betathromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
  • Increased thyroid binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels 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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
  • Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
  • Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels.
  • Impaired glucose tolerance.


E. Carcinogenesis, Mutagenesis, Impairment of Fertility 

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis and liver.

F. Pregnancy 

E-CONIK should not be used during pregnancy. 

G. Nursing Mothers 

E-CONIK should not be used during lactation. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. 

H. Pediatric Use 

Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and effectiveness in pediatric patients have not otherwise been established.

Large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, which could result in short stature if treatment is initiated before the completion of physiologic puberty in normally developing children. If estrogen is administered to patients whose bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended during estrogen administration.

Estrogen treatment of prepubertal girls also induces premature breast development and vaginal cornification, and may induce vaginal bleeding. In boys, estrogen treatment may modify the normal pubertal process and induce gynecomastia. (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.)

I. Geriatric Use

Risk for probable dementia. However, it is unknown whether these findings apply to younger postmenopausal women.


Drug Interactions

Data from a single-dose drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic dispositions of both drugs are not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with conjugated estrogens.

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as, phenobarbital, carbamazepine and rifampin, 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 erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in side effects.


ADVERSE REACTIONS

1. Genitourinary system 

  • Abnormal uterine bleeding/spotting
  • Dysmenorrhea/pelvic pain
  • Increase in size of uterine leiomyomata.
  • Vaginitis, including vaginal candidiasis.
  • Change in amount of cervical secretion.
  • Change in cervical ectropion.
  • Ovarian cancer
  • Endometrial hyperplasia
  • Endometrial cancer

2. Breasts 

  • Tenderness, enlargement, pain, discharge, galactorrhea.
  • Fibrocystic breast changes
  • Breast cancer

3. Cardiovascular 

  • Deep and superficial venous thrombosis
  • Pulmonary embolism
  • Thrombophlebitis
  • Myocardial infarction
  • Stroke
  • Increase in blood pressure

4. Gastrointestinal 

  • Nausea, vomiting
  • Abdominal cramps, bloating
  • Cholestatic jaundice
  • Increased incidence of gallbladder disease.
  • Pancreatitis
  • Enlargement of hepatic hemangiomas.
  • Ischemic colitis

5. Skin 

  • Chloasma or melasma that may persist when drug is discontinued.
  • Erythema multiforme
  • Erythema nodosum
  • Hemorrhagic eruption
  • Loss of scalp hair.
  • Hirsutism
  • Pruritus, rash

6. Eyes 

  • Retinal vascular thrombosis
  • Intolerance to contact lenses.

7. Central Nervous System 

  • Headache
  • Migraine
  • Dizziness
  • Mental depression
  • Exacerbation of chorea
  • Nervousness
  • Mood disturbances
  • Irritability
  • Exacerbation of epilepsy
  • Dementia
  • Possible growth potentiation of benign meningioma.

8. Miscellaneous 

  • Increase or decrease in weight
  • Glucose intolerance
  • Aggravation of porphyria
  • Edema
  • Arthralgias
  • Leg cramps
  • Changes in libido
  • Urticaria, angioedema, anaphylactoid/anaphylactic reactions
  • Hypocalcemia (preexisting condition)
  • Exacerbation of asthma
  • Increased triglycerides

OVERDOSAGE 
Overdosage of estrogen may cause nausea and vomiting, breast tenderness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in females. Treatment of overdose consists of discontinuation of E-CONIK together with institution of appropriate symptomatic care.


E-CONIK may be taken without regard to meals.

Packing: Blister of 28 tablets.
Storage: Store in a well closed container at controlled room temperature.

 

 
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