Estrogens, Conjugated

Estrogens increase the liver's ability to manufacture factors that promote the clotting of blood. Because of this, patients receiving warfarin (Coumadin), a drug that thins the blood and prevents clotting by reducing clotting factors, need to be monitored for loss of the blood thinning effect if treatment with an estrogen is begun.

Rifampin (Rifadin), barbiturates, carbamazepine (Tegretol), griseofulvin (Grifulvin), phenytoin (Dilantin), St. John's wort, and primidone all increase the elimination of estrogen by enhancing the liver's ability to eliminate estrogens. Use of any of these medications with estrogens may result in a reduction of the beneficial effects of estrogens.

Conversely, drugs such as erythromycin, ketoconazole (Nizoral), itraconazole (Sporanox), and ritonavir (Norvir) may reduce the elimination of estrogens by the liver and lead to increased levels of estrogens in the blood.

Grapefruit juice also may increase levels of estrogen by increasing the absorption of estrogens from the intestine. Increased levels of estrogens in the blood may result in more estrogen-related side effects.

General

• A progestin generally is added to estrogen therapy (HRT) in women with an intact uterus.101 104 105 107 121 Addition of a progestin for ≥10 days per cycle of estrogen or daily with estrogen reduces incidence of endometrial hyperplasia and attendant risk of endometrial carcinoma in women with an intact uterus.101 104 105 107 121

• As an alternative to progestin, use of bazedoxifene (an estrogen agonist-antagonist) in fixed combination with conjugated estrogens reduces risk of endometrial hyperplasia.261 262 263

• ERT is appropriate in women who have undergone a hysterectomy (to avoid unnecessary exposure to progestins).101 104 105 107 121

Administration

Conjugated estrogens USP usually administered orally; may also administer intravaginally or by deep IM or slow IV injection.101 104 105 107

Administer synthetic conjugated estrogens A and synthetic conjugated estrogens B orally.106 121

Estrogen therapy generally is administered in a continuous daily dosage regimen or, alternatively, in a cyclic regimen.101 105 107 When administered cyclically, estrogen usually is given once daily for 3 weeks followed by 1 week without the drug or once daily for 25 days followed by 5 days off; regimen is repeated as necessary.101 105

When parenteral administration of conjugated estrogens USP is required, IV injection is preferred because of the more rapid response compared with IM injection.104

Oral Administration

Oral preparations containing medroxyprogesterone acetate in combination with conjugated estrogens USP as monophasic or biphasic regimens are commercially available in a mnemonic dispensing package to aid user in complying with the prescribed dosage schedule.107

Oral preparation containing bazedoxifene acetate in fixed combination with conjugated estrogens is commercially available in a 30-day package including 2 blister packs of 15 tablets each.262

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by direct IV injection.104

Reconstitute vial containing 25 mg of conjugated estrogens USP with 5 mL of sterile water for injection.104 Do not shake vigorously.104 Administer immediately after reconstitution.104

Administer slowly (to avoid flushing reaction).104

IM Administration

Administer by deep IM injection.104

Reconstitute vial containing 25 mg of conjugated estrogens USP with 5 mL of sterile water for injection.104 Do not shake vigorously.104 Administer immediately after reconstitution.104

Vaginal Administration

Administer intravaginally as a vaginal cream.105

Dosage

Individualize dosage according to the condition being treated and the tolerance and therapeutic response of the patient.101 104 105 106 107 121

To minimize risk of adverse effects, use the lowest possible effective dosage.101 104 105 106 107 121 Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, limit estrogen, estrogen/progestin, or conjugated estrogens in fixed combination with bazedoxifene to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman.101 104 105 107 121 262

Periodically reevaluate use of estrogen, estrogen/progestin, or conjugated estrogens in fixed combination with bazedoxifene (i.e., at 3- to 6-month intervals).101 104 105 107 121 262

Pediatric Patients

Conjugated estrogens USP: 0.15 mg daily may induce breast development.101 Increase dosage at 6- to 12-month intervals to achieve appropriate bone age advancement and epiphyseal closure.101

Conjugated estrogens USP: 0.625 mg daily (with progestins) sufficient to induce artificial cyclic menses and to maintain bone mineral density (BMD) after skeletal maturity.101

Adults

Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off).101 Adjust dosage based on patient response.101

Synthetic conjugated estrogens A: Initially, 0.45 mg daily.106 May increase dosage up to 1.25 mg daily.106

Synthetic conjugated estrogens B: Initially, 0.3 mg daily.121 266 May increase dosage up to 1.25 mg daily.266 Adjust dosage based on patient response.121 266

Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily.107 Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.107

Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15–28 of the cycle.107

Conjugated estrogens in fixed combination with bazedoxifene acetate: Conjugated estrogens 0.45 mg with bazedoxifene 20 mg once daily.262

Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off).101 Adjust dosage based on patient response.101

Synthetic conjugated estrogens A: 0.3 mg daily.106

Synthetic conjugated estrogens B: 0.3 mg daily.266

Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily.107 Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.107

Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15–28 of the cycle.107

Conjugated estrogens USP: 0.5–2 g daily in cyclic regimen (3 weeks on, 1 week off).105

Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off).101 Adjust dosage based on clinical and BMD response.101

Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily.107 Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.107 Adjust dosage based on clinical and BMD response.107

Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15–28 of the cycle.107

Conjugated estrogens in fixed combination with bazedoxifene acetate: Conjugated estrogens 0.45 mg with bazedoxifene 20 mg once daily.262

Conjugated estrogens USP: 0.3–0.625 mg daily in a cyclic regimen (3 weeks on, 1 week off).101 Adjust dosage based on symptom severity and endometrial responsiveness.101

Conjugated estrogens USP: 1.25 mg daily in a cyclic regimen.101 Adjust dosage based on symptom severity and clinical response.101

Conjugated estrogens USP: 10 mg 3 times daily for ≥3 months.101

Conjugated estrogens USP: 1.25–2.5 mg 3 times daily.101

Conjugated estrogens USP: 25 mg; can repeat dose in 6–12 hours.104

Storage

Oral

20–25°C (may be exposed to 15–30°C).101 106 107 121

Parenteral

2–8°C.104

Vaginal

20–25°C (may be exposed to 15–30°C).105

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Stated to be incompatible with protein hydrolysate, ascorbic acid, or any solution with an acid pH.104

• Conjugated estrogens USP is a mixture of conjugated equine estrogens obtained from natural sources and occurring as the sodium salts of the water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mare’s urine.101 It is a mixture of sodium estrone sulfate and sodium equilin sulfate that also contains 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, equilenin, 17α-dihydroequilenin, 17β-dihydroequilenin, δ8,9-dehydroestrone, and 17β-estradiol.101

• Synthetic conjugated estrogens A is a mixture of conjugated estrogens prepared synthetically from plant sources (i.e., soy and yams).106 It contains the sodium salts of water-soluble estrogen sulfates blended into a 9-component mixture of estrone sulfate and sodium equilin sulfate as well as the concomitant components 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, 17α-dihydroequilenin, 17β-dihydroequilenin, equilenin, and 17β-estradiol as sodium sulfate conjugates.106

• Synthetic conjugated estrogens B is a mixture of conjugated estrogens prepared synthetically from plant sources.121 122 It contains the sodium salts of water-soluble estrogen sulfates blended into a 10-component mixture of estrone sulfate and sodium equilin sulfate as well as the concomitant components 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, 17α-dihydroequilenin, 17β-dihydroequilenin, equilenin, 17β-estradiol, and δ8,9-dehydroestrone as sodium sulfate conjugates.121 This mixture contains the 10 estrogenic substances present in currently available commercial preparations of conjugated estrogens USP.121

• Exogenous estrogens elicit, to varying degrees, all the pharmacologic responses usually produced by endogenous estrogens.a

Effects on vasomotor symptoms.

In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2805 postmenopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight treatment groups of 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 7 moderate to severe hot flushes daily or at least 50 moderate to severe hot flushes during the week before randomization. PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg were shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms. Table 3 shows the adjusted mean number of hot flushes in the PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, 0.3 mg/1.5 mg, and placebo groups during the initial 12-week period.

Effects on vulvar and vaginal atrophy.

Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo were statistically significant (p < 0.001) for all treatment groups (conjugated estrogens alone and conjugated estrogens/medroxyprogesterone acetate treatment groups).

Effects on the endometrium.

In a 1-year clinical trial of 1376 women (average age 54.0 ± 4.6 years) randomized to PREMPRO 0.625 mg/2.5 mg (n=340), PREMPRO 0.625 mg/5 mg (n=338), PREMPHASE 0.625 mg/5 mg (n=351), or Premarin 0.625 mg alone (n=347), results of evaluable biopsies at 12 months (n=279, 274, 277, and 283, respectively) showed a reduced risk of endometrial hyperplasia in the two PREMPRO treatment groups (less than 1%) and in the PREMPHASE treatment group (less than 1%; 1% when focal hyperplasia was included) compared to the Premarin group (8%; 20% when focal hyperplasia was included). See Table 4.

In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, 2001 women (average age 53.3 ± 4.9 years) of whom 88% were Caucasian were treated with either Premarin 0.625 mg alone (n = 348), Premarin 0.45 mg alone (n = 338), Premarin 0.3 mg alone (n = 326) or PREMPRO 0.625 mg/2.5 mg (n = 331), PREMPRO 0.45 mg/1.5 mg (n = 331) or PREMPRO 0.3 mg/1.5 mg (n = 327). Results of evaluable endometrial biopsies at 12 months showed a reduced risk of endometrial hyperplasia or cancer in the PREMPRO treatment groups compared with the corresponding Premarin alone treatment groups, except for the PREMPRO 0.3 mg/1.5 mg and Premarin 0.3 mg alone groups, in each of which there was only 1 case. See Table 5.

No endometrial hyperplasia or cancer was noted in those patients treated with the continuous combined regimens who continued for a second year in the osteoporosis and metabolic substudy of the HOPE study. See Table 6.

Effects on uterine bleeding or spotting.

The effects of PREMPRO on uterine bleeding or spotting, as recorded on daily diary cards, were evaluated in 2 clinical trials. Results are shown in Figures 1 and 2.

Note:  The percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF).

Note:  The percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF).

Effects 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 PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg or 0.3 mg/1.5 mg, comparable doses of Premarin alone, or placebo. Prevention of bone loss was assessed by measurement of bone mineral density (BMD), primarily at the anteroposterior lumbar spine (L 2 to L 4 ). 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 4 BMD endpoints. These significant differences were seen at cycles 6, 13, 19, and 26. With PREMPRO, the mean percent increases in the primary efficacy measure (L 2 to L 4 BMD) at the final on-therapy evaluation (cycle 26 for those who completed and the last available evaluation for those who discontinued early) were 3.28% with 0.625 mg/2.5 mg, 2.18% with 0.45 mg/1.5 mg, and 1.71% with 0.3 mg/1.5 mg. The placebo group showed a mean percent decrease from baseline at the final evaluation of 2.45%. These results show that the lower dose regimens of PREMPRO were effective in increasing L 2 to L 4 BMD compared with placebo and, therefore, support the efficacy of lower doses of PREMPRO.

The analysis for the other 3 BMD endpoints yielded mean percent changes from baseline in femoral trochanter that were generally larger than those seen for L 2 to L 4 and changes in femoral neck and total body that were generally smaller than those seen for L 2 to L 4 . Significant differences between groups indicated that each of the PREMPRO treatment groups was more effective than placebo for all 3 of these additional BMD endpoints. With regard to femoral neck and total body, the continuous combined treatment groups all showed mean percent increases in BMD while the placebo group showed mean percent decreases. For femoral trochanter, each of the PREMPRO groups showed a mean percent increase that was significantly greater than the small increase seen in the placebo group. The percent changes from baseline to final evaluation are shown in Table 7.

Figure 3 shows the cumulative percentage of subjects with percent changes from baseline in spine BMD equal to or greater than the percent change shown on the x-axis.

The mean percent changes from baseline in L 2 to L 4 BMD for women who completed the bone density study are shown with standard error bars by treatment group in Figure 4. Significant differences between each of the PREMPRO dosage groups and placebo were found at cycles 6, 13, 19, and 26.

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; only with PREMPRO 0.625 mg/2.5 mg and 0.45 mg/1.5 mg were there significantly larger mean decreases than with placebo at 3 or more of the 4 time points.

Women's Health Initiative Studies.

A substudy of the Women's Health Initiative (WHI) enrolled 16,608 predominantly healthy postmenopausal women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic) to assess the risks and benefits of the use of PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate per day) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of PREMPRO on menopausal symptoms. The estrogen plus progestin substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results are presented in Table 8 below:

For those outcomes included in the "global index", the absolute excess risks per 10,000 women-years in the group treated with PREMPRO were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNING , WARNINGS , and PRECAUTIONS .)

Women's Health Initiative Memory Study.

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of PREMPRO (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING and WARNINGS , Dementia .)

PREMPRO or PREMPHASE therapy is indicated in women who have a uterus for the:

1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
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.
3. 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. (See CLINICAL PHARMACOLOGY , Clinical Studies .)
   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 may be 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.

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 with estrogen-alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g., 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 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. In the HOPE study, the mean percent increase from baseline in serum triglycerides after one year of treatment with PREMPRO 0.625 mg/2.5 mg, 0.45 mg/1.5 mg, and 0.3 mg/1.5 mg compared with placebo were 32.8, 24.8, 23.3, and 10.7, respectively. After two years of treatment, the mean percent changes were 33.0, 17.1, 21.6, and 5.5, respectively.
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/progestins 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 that after an average follow-up of 5.6 years, the relative risk of ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95% confidence interval 0.77-3.24) but was not statistically significant. The absolute risk for estrogen plus progestin versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen-only products, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.
9. Exacerbation of endometriosis.
   Endometriosis may be exacerbated with administration of estrogen therapy.
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 women with these conditions.

B. Patient Information

Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe PREMPRO or PREMPHASE.

C. Laboratory Tests

Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH).

D. Drug/Laboratory Test Interactions

1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-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.
7. Aminoglutethimide administered concomitantly with medroxyprogesterone acetate (MPA) may significantly depress the bioavailability of MPA.

E. Carcinogenesis, Mutagenesis, Impairment of Fertility

(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 breasts, uterus, cervix, vagina, testis, and liver.

In a two-year oral study of medroxyprogesterone acetate (MPA) in which female rats were exposed to dosages of up to 5000 mcg/kg/day in their diets (50 times higher - based on AUC values - than the level observed experimentally in women taking 10 mg of MPA), a dose-related increase in pancreatic islet cell tumors (adenomas and carcinomas) occurred. Pancreatic tumor incidence was increased at 1000 and 5000 mcg/kg/day, but not at 200 mcg/kg/day.

A decreased incidence of spontaneous mammary gland tumors was observed in all three MPA-treated groups, compared with controls, in the two-year rat study. The mechanism for the decreased incidence of mammary gland tumors observed in the MPA-treated rats may be linked to the significant decrease in serum prolactin concentration observed in rats.

Beagle dogs treated with MPA developed mammary nodules, some of which were malignant. Although nodules occasionally appeared in control animals, they were intermittent in nature, whereas the nodules in the drug-treated animals were larger, more numerous, persistent, and there were some breast malignancies with metastases. It is known that progestogens stimulate synthesis and release of growth hormone in dogs. The growth hormone, along with the progestogen, stimulates mammary growth and tumors. In contrast, growth hormone in humans is not increased, nor does growth hormone have any significant mammotrophic role. No pancreatic tumors occurred in dogs.

F. Pregnancy

PREMPRO and PREMPHASE should not be used during pregnancy. (See CONTRAINDICATIONS .)

G. Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogen and progestin have been identified in the milk of mothers receiving these drugs. Caution should be exercised when PREMPRO or PREMPHASE are administered to a nursing woman.

H. Pediatric Use

PREMPRO and PREMPHASE are not indicated in children.

I. Geriatric Use

Of the total number of subjects in the estrogen plus progestin substudy of the Women's Health Initiative study, 44% (n = 7320) were 65 years and over, while 6.6% (n = 1,095) were 75 years and over (see CLINICAL PHARMACOLOGY , Clinical Studies ). There was a higher incidence of stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age.

In the Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 4,532 women aged 65 to 79 years was randomized to PREMPRO (0.625 mg/2.5 mg) or placebo. A population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to Premarin (0.625 mg) or placebo. In the planned analysis, pooling the events in women receiving Premarin or PREMPRO in comparison to those in women on placebo, the overall relative risk (RR) for probable dementia was 1.76 (95% CI 1.19-2.60). In the estrogen-alone group, after an average follow-up of 5.2 years a RR of 1.49 (95% CI 0.83-2.66) for probable dementia was observed compared to placebo. In the estrogen-plus-progestin group, after an average follow-up of 4 years, a RR of 2.05 (95% CI 1.21-3.48) for probable dementia was observed compared to placebo. Since this study was conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS , Dementia .)

With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric patients involved in studies utilizing Premarin and medroxyprogesterone acetate to determine whether those over 65 years of age differ from younger subjects in their response to PREMPRO or PREMPHASE.

See BOXED WARNING , 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 with 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 1-year clinical trial that included 678 postmenopausal women treated with PREMPRO, 351 postmenopausal women treated with PREMPHASE, and 347 postmenopausal women treated with Premarin, the following adverse events occurred at a rate >/= 5% (see Table 9):

During the first year of a 2-year clinical trial with 2333 postmenopausal women between 40 and 65 years of age (88% Caucasian), 2001 women received continuous regimens of either 0.625 mg of CE with or without 2.5 mg MPA, or 0.45 mg or 0.3 mg of CE with or without 1.5 mg MPA, and 332 received placebo tablets. Table 10 summarizes adverse events that occurred at a rate >/= 5% in at least 1 treatment group.

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, change in amount of cervical secretion, premenstrual-like syndrome, cystitis-like syndrome, increase in size of uterine leiomyomata, vaginal candidiasis, amenorrhea, changes in cervical erosion, 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, cholestatic jaundice, changes in appetite, vomiting, abdominal cramps, bloating, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic hemangiomas.
5. Skin
   Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair, hirsutism, itching, urticaria, pruritus, generalized rash, rash (allergic) with and without pruritus, acne.
6. Eyes
   Neuro-ocular lesions, e.g., retinal vascular thrombosis and optic neuritis, intolerance of contact lenses.
7. Central Nervous System (CNS)
   Headache, dizziness, mental depression, mood disturbances, anxiety, irritability, nervousness, migraine, chorea, insomnia, somnolence, exacerbation of epilepsy, dementia.
8. Miscellaneous
   Increase or decrease in weight, edema, changes in libido, fatigue, backache, reduced carbohydrate tolerance, aggravation of porphyria, pyrexia, urticaria, angioedema, anaphylactoid/anaphylactic reactions, hypocalcemia, exacerbation of asthma, increased triglycerides.

Serious ill effects have not been reported following acute ingestion of large doses of estrogen/progestin-containing drug products by young children. Overdosage of estrogen/progestin may cause nausea and vomiting, and withdrawal bleeding may occur in females.