Estrogens, conjugated, synthetic A

Name: Estrogens, conjugated, synthetic A

Description

Synthetic conjugated estrogens, A tablets contain a blend of nine (9) synthetic estrogenic substances. The estrogenic substances are sodium estrone sulfate, sodium equilin sulfate, sodium 17(alpha)-dihydroequilin sulfate, sodium 17(alpha)-estradiol sulfate, sodium 17(beta)-dihydroequilin sulfate, sodium 17(alpha)-dihydroequilenin sulfate, sodium 17(beta)-dihydroequilenin sulfate, sodium equilenin sulfate and sodium 17(beta)-estradiol sulfate.

The structural formulae for these estrogens are:

Tablets for oral administration, are available in 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg and 1.25 mg strengths of synthetic conjugated estrogens, A. Tablets also contain the following inactive ingredients: ethylcellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch, titanium dioxide, and triethyl citrate.

-0.3 mg tablets also contain FD&C Blue No. 2 aluminum lake and D&C Yellow No. 10 aluminum lake.

-0.45 mg tablets also contain FD&C Yellow No. 6/Sunset Yellow FCF lake.

-0.625 mg tablets also contain FD&C Red No. 40 aluminum lake.

-0.9 mg tablets do not contain additional color additives.

-1.25 mg tablets also contain FD&C Blue No. 2 aluminum lake.

Clinical Pharmacology

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, 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 hormones seen in postmenopausal women.

Indications and Usage

Cenestin therapy is indicated for the:

  1. Treatment of moderate-to-severe vasomotor symptoms associated with the menopause.
    • 0.45 mg Cenestin
    • 0.625 mg Cenestin
    • 0.9 mg Cenestin
    • 1.25 mg Cenestin
  2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
    • 0.3 mg Cenestin

Contraindications

Cenestin should not be used in individuals with any of the following conditions:

  1. Undiagnosed abnormal genital bleeding.
  2. Known, suspected, or history of cancer of the breast.
  3. Known or suspected estrogen-dependent neoplasia.
  4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.
  5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
  6. Liver dysfunction or disease.
  7. Cenestin therapy should not be used in patients with known hypersensitivity to its ingredients.
  8. Known or suspected pregnancy. There is no indication for Cenestin in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See PRECAUTIONS .)

Precautions

  1. 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 in estrogen replacement regimens. These include:
      1. A possible increased risk of breast cancer.
      2. Adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL).
      3. 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 with 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.
    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 T 4 and T 3 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. Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a 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. Use of estrogen-only products, in particular for ten or more years, has been associated with an increased risk of ovarian cancer in some epidemiological studies. Other studies did not show a significant association. Data are insufficient to determine whether there is an increased risk with estrogen/progestin combination therapy in postmenopausal women.
    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. Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
  2. Patient Information
    Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Cenestin.
  3. Laboratory Tests
    Estrogen administration should be initiated at the lowest dose for the approved indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH).
  4. Drug/Laboratory Test Interactions
    1. 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, IIVII-X complex, and beta-thromboglobulin; 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.
    2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels, as measured by protein-bound iodine (PBI), T 4 levels (by column or by radioimmunoassay) or T 3 levels by radioimmunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG. Free T 4 and free T 3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
    3. 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).
    4. Increased plasma HDL and HDL 2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels.
    5. Impaired glucose tolerance.
    6. Reduced response to metyrapone test.
  5. Carcinogenesis, Mutagenesis, Impairment of Fertility
    Long-term continuous administration of estrogen, with and without progestin, in women, with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS , WARNINGS and PRECAUTIONS .)
    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.
  6. Pregnancy
    Cenestin should not be used in pregnancy. (See CONTRAINDICATIONS .)
  7. Nursing Mothers
    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. Caution should be exercised when Cenestin is administered to a nursing woman.
  8. Pediatric Use
    Cenestin is not indicated in children.
  9. Geriatric Use
    There have not been sufficient numbers of geriatric patients involved in studies utilizing Cenestin to determine whether those over 65 years of age differ from younger subjects in their response to Cenestin.

Adverse Reactions

See BOXED WARNINGS , WARNINGS and PRECAUTIONS .

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

In a 12-week clinical trial that included 72 women treated with 0.625 mg and 2 x 0.625 mg Cenestin and 48 women treated with placebo, adverse events that occurred at a rate of >/= 5% are summarized in Table 5.

Table 5
Number (%) of Patients with Adverse Events With >/=5% Occurrence Rate By

Body System and Treatment Group
Body System
 Adverse Event
Cenestin *
0.625 mg and
2 × 0.625 mg
n (%)
Placebo
n (%)
Total
n (%)
Number of Patients Who Received Medication 72 (100) 48 (100) 120 (100)
Number of Patients With Adverse Events 68  (94) 43  (90) 111  (93)
Number of Patients Without Any Adverse Events 4   (6) 5  (10) 9   (8)
Body As A Whole
 Abdominal Pain 20  (28) 11  (23) 31  (26)
 Asthenia 24  (33) 20  (42) 44  (37)
 Back Pain 10  (14) 6  (13) 16  (13)
 Fever 1   (1) 3   (6) 4   (3)
 Headache 49  (68) 32  (67) 81  (68)
 Infection 10  (14) 5  (10) 15  (13)
 Pain 8  (11) 9  (19) 17  (14)
Cardiovascular System
 Palpitation 15  (21) 13  (27) 28  (23)
Digestive System
 Constipation 4   (6) 2   (4) 6   (5)
 Diarrhea 4   (6) 0   (0) 4   (3)
 Dyspepsia 7  (10) 3   (6) 10   (8)
 Flatulence 21  (29) 14  (29) 35  (29)
 Nausea 13  (18) 9  (19) 22  (18)
 Vomiting 5   (7) 1   (2) 6   (5)
Metabolic and Nutritional
 Peripheral Edema 7  (10) 6  (13) 13  (11)
Musculoskeletal System
 Arthralgia 18  (25) 13  (27) 31  (26)
 Myalgia 20  (28) 15  (31) 35  (29)
Nervous System
 Depression 20  (28) 18  (38) 38  (32)
 Dizziness 8  (11) 5  (10) 13  (11)
 Hypertonia 4   (6) 0   (0) 4   (3)
 Insomnia 30  (42) 23  (48) 53  (44)
 Leg Cramps 7  (10) 3   (6) 10   (8)
 Nervousness 20  (28) 20  (42) 40  (33)
 Paresthesia 24  (33) 15  (31) 39  (33)
 Vertigo 12  (17) 12  (25) 24  (20)
Respiratory System
 Cough Increased 4   (6) 1   (2) 5   (4)
 Pharyngitis 6   (8) 4   (8) 10   (8)
 Rhinitis 6   (8) 7  (15) 13  (11)
Skin and Appendages
 Rash 3   (4) 3   (6) 6   (5)
Urogenital System
 Breast Pain 21  (29) 7  (15) 28  (23)
 Dysmenorrhea 4   (6) 3   (6) 7   (6)
 Metrorrhagia 10  (14) 3   (6) 13  (11)
*Combined results for 0.625 mg and 2 × 0.625 mg Cenestin Tablets

In a second 12-week clinical trial that included 52 women treated with 0.45 mg Cenestin and 51 women treated with placebo, adverse events that occurred at a rate of >5% are summarized in Table 6

Table 6
Number (%) of Patients with a >/=5% Occurrence Rate
By Body System and Treatment Group
Body System and Term        Cenestin
       0.45 mg
         Control     p-value
 Any Adverse Event % 40 (75.5%) 39 (76.5%) 1.0000
Body As A Whole 20 (37.7%) 24 (47.1%) 0.4275
 Asthenia 6 (11.3%) 7 (13.7%) 0.7731
 Headache 6 (11.3%) 8 (15.7%) 0.5748
 Infection 1  (1.9%) 6 (11.8%) 0.0576
 Pain 6 (11.3%) 1  (2.0%) 0.1128
 Pain abdominal 5  (9.4%) 3  (5.9%) 0.7159
Cardiovascular 5  (9.4%) 10 (19.6%) 0.1695
 Palpitations 3  (5.7%) 3  (5.9%) 1.0000
 Vasodilations 2  (3.8%) 4  (7.8%) 0.4324
Digestive 8 (15.1%) 7 (13.7%) 1.0000
 Nausea 5  (9.4%) 2  (3.9%) 0.4374
Metabolic and Nutritional 5  (9.4%) 3  (5.9%) 0.7159
 Weight increase 3  (5.7%) 2  (3.9%) 1.0000
Musculoskeletal 5  (9.4%) 6 (11.8%) 0.7582
 Arthralgia 5  (9.4%) 5  (9.8%) 1.0000
 Myalgia 2  (3.8%) 6 (11.8%) 0.1566
Neurological 15 (28.3%) 19 (37.3%) 0.4044
 Anxiety 3  (5.7%) 1  (2.0%) 0.6179
 Depression 2  (3.8%) 7 (13.7%) 0.0895
 Insomnia 3  (5.7%) 5  (9.8%) 0.4839
 Nervousness 2  (3.8%) 7 (13.7%) 0.0895
 Paresthesia 4  (7.5%) 3  (5.9%) 1.0000
 Vertigo 3  (5.7%) 3  (5.9%) 1.0000
Respiratory 10 (18.9%) 6 (11.8%) 0.4173
 Upper Respiratory Tract Infection 7 (13.2%) 1  (2.0%) 0.0603
 Rhinitis 3  (5.7%) 2  (3.9%) 1.0000
 Pharyngitis 1  (1.9%) 3  (5.9%) 0.3581
Urogenital 19 (35.8%) 7 (13.7%) 0.0124
 Endometrial thickening 10 (18.9%) 4  (7.8%) 0.1503
 Vaginitis 4  (7.5%) 1  (2.0%) 0.3632
P-value by Fisher's Exact (2-tail) Test
If a subject experiences the same event more than once, the first occurrence is tabulated.

The following additional adverse reactions have been reported with estrogen and/or progestin therapy:

  1. Genitourinary system.
    Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.
  2. Breasts.
    Tenderness, enlargement, pain, nipple 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.
  5. Skin.
    Chloasma or melasma, which 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; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy.
  8. Miscellaneous.
    Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthalgias; leg cramps; changes in libido; anaphylactoid/anaphylactic reactions including urticaria and angioedema; hypocalcemia; exacerbation of asthma; increased triglycerides.
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