PREMARIN® (conjugated estrogens)Vaginal Cream in a nonliquefying base

premarin (Conjugated Estrogenscream 
[Wyeth Pharmaceuticals, Inc.]


NOTE: PATIENT INFORMATION LEAFLET ATTACHED.

Rx only

WARNING

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. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)

CARDIOVASCULAR AND OTHER RISKS

Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Dementia.)

The estrogen alone substudy of Women's Health Initiative (WHI) reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of treatment with daily oral conjugated estrogens (CE 0.625 mg), relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders.)

The estrogen plus progestin substudy of WHI reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and DVT in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily CE 0.625 mg combined with medroxyprogesterone acetate (MPA 2.5 mg), relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.)

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE 0.625 mg alone and during 4 years of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. 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.

DESCRIPTION

Each gram of PREMARIN® (conjugated estrogens) Vaginal Cream contains 0.625 mg conjugated estrogens, USP in a nonliquefying base containing cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin, and mineral oil. Premarin Vaginal Cream is applied intravaginally.

Premarin (conjugated estrogens) Vaginal Cream contains a mixture of conjugated estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains as concomitant components, as sodium sulfate conjugates, 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin.

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 estrogen 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

A. Absorption

Conjugated estrogens are water-soluble and are well-absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism.

B. 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.

C. 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 portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

D. Excretion

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

E. Special Populations

No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

F. Drug Interactions

Data from a single-dose drug-drug interaction study involving oral 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 St. John's Wort preparations (Hypericum perforatum), 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.

CLINICAL STUDIES

Women's Health Initiative Studies

The Women’s Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of daily oral conjugated estrogens (CE 0.625 mg) alone or in combination with medroxyprogesterone acetate (MPA 2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction [MI], silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in CE/MPA substudy), colorectal cancer, hip fracture, or death due to other causes. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The estrogen alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen alone in predetermined primary endpoints. Results of the estrogen alone substudy, which included 10,739 women (average age of 63 years, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 6.8 years, are presented in Table 1.

TABLE 1. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN ALONE SUBSTUDY OF WHI
EventRelative Risk
CE vs. Placebo
(95% nCIa)
Placebo
n = 5,429
CE
n = 5,310
Absolute Risk per 10,000
Women-Years

aNominal confidence intervals unadjusted for multiple looks and multiple comparisons.
bResults are based on centrally adjudicated data for an average follow-up of 7.1 years.
cResults are based on an average follow-up of 6.8 years.
dNot included in Global Index.
eAll deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.
fA subset of the events was combined in a “global index,” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.

CHD eventsb 0.95 (0.79-1.16)56 53
  Non-fatal MIb0.91 (0.73-1.14)43 40
  CHD deathb1.01 (0.71-1.43)16 16
Strokec1.37 (1.09-1.73) 33 45
  Ischemicb1.55 (1.19–2.01)2538
Deep vein thrombosisb,d1.47 (1.06-2.06) 15 23
Pulmonary embolismb1.37 (0.90-2.07) 10 14
Invasive breast cancerb 0.80 (0.62-1.04) 34 28
Colorectal cancerc1.08 (0.75-1.55)16 17
Hip fracturec0.61 (0.41-0.91)1711
Vertebral fracturesc,d0.62 (0.42-0.93)17 11
Total fracturesc,d0.70 (0.63-0.79)195139
Death due to other causesc,e1.08 (0.88-1.32) 50 53
Overall mortalityc,d1.04 (0.88-1.22) 78 81
Global Indexc,f1.01 (0.91-1.12) 190 192

For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE alone were 12 more strokes while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The absolute excess risk of events included in the “global index” was a nonsignificant 2 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

Final centrally adjudicated results for CHD events and centrally adjudicated results for invasive breast cancer incidence from the estrogen alone substudy, after an average follow-up of 7.1 years, reported no overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE alone compared with placebo (see Table 1).

Centrally adjudicated results for stroke events from the estrogen alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE alone compared to placebo. Estrogen alone increased the risk for ischemic stroke, and this excess was present in all subgroups of women examined (see Table 1).

The estrogen plus progestin substudy was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years (relative risk [RR] 1.15, 95 percent nCI 1.03-1.28).

For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 7 fewer colorectal cancers and 5 fewer hip fractures. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

Results of the estrogen plus progestin substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 2. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

TABLE 2. RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN PLUS PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARSa
Event Relative Risk
CE/MPA vs. Placebo
(95% nCIb)
Placebo
n = 8,102
CE/MPA
n = 8,506
Absolute Risk per 10,000
Women-Years

aResults are based on centrally adjudicated data. Mortality data was not part of the adjudicated data; however, data at 5.2 years of follow-up showed no difference between the groups in terms of all-cause mortality (RR 0.98, 95 percent nCI 0.82-1.18).
bNominal confidence intervals unadjusted for multiple looks and multiple comparisons.
cIncludes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer.

CHD events 1.24 (1.00-1.54)33 39
  Non-fatal MI1.28 (1.00-1.63)25 31
  CHD death1.10 (0.70-1.75)8 8
All strokes1.31 (1.02-1.68) 24 31
Ischemic stroke1.44 (1.09-1.90)18 26
Deep vein thrombosis1.95 (1.43-2.67) 13 26
Pulmonary embolism2.13 (1.45-3.11)8 18
Invasive breast cancerc1.24 (1.01-1.54)33 41
Invasive colorectal cancer 0.56 (0.38-0.81) 169
Endometrial cancer0.81 (0.48-1.36)7 6
Cervical cancer1.44 (0.47-4.42)1 2
Hip fracture0.67 (0.47-0.96)16 11
Vertebral fractures 0.65 (0.46-0.92) 17 11
Lower arm/wrist fractures0.71 (0.59-0.85) 6244
Total fractures0.76 (0.69-0.83)199152

Women's Health Initiative Memory Study

The estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45 percent, age 65 to 69 years; 36 percent, 70 to 74 years; 19 percent, 75 years of age and older) to evaluate the effects of daily CE 0.625 mg on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen alone group was 1.49 (95 percent CI 0.83–2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent, age 65 to 69 years; 35 percent, 70 to 74 years; 18 percent were 75 years of age and older) to evaluate the effects of daily CE/MPA 0.625 mg conjugated estrogens/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 plus 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 1.21–3.48) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

INDICATIONS AND USAGE

Premarin (conjugated estrogens) Vaginal Cream therapy is indicated in the treatment of atrophic vaginitis and kraurosis vulvae.

CONTRAINDICATIONS

Premarin Vaginal Cream therapy should not be used in women 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 (within past year) arterial thromboembolic disease (for example, stroke, myocardial infarction).
  6. Liver dysfunction or disease.
  7. Known hypersensitivity to any of the ingredients in Premarin Vaginal Cream.
  8. Known or suspected pregnancy.

WARNINGS

See BOXED WARNINGS.

Systemic absorption occurs with the use of Premarin Vaginal Cream. The warnings, precautions, and adverse reactions associated with oral Premarin treatment should be taken into account.

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 (CE 0.625 mg) compared to placebo (44 versus 32 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted. (See CLINICAL STUDIES.)

In the estrogen plus progestin substudy of WHI, a statistically significant increased risk of stroke was reported in women receiving daily CE 0.625 mg plus medroxyprogesterone acetate (MPA/2.5 mg) compared to placebo (31 versus 24 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. (See CLINICAL STUDIES.)

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. (See CLINICAL STUDIES.)

In the estrogen plus progestin substudy of WHI, no statistically significant increase of CHD events was reported in women receiving CE/MPA compared to women receiving placebo (39 versus 33 per 10,000 women years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/progestin Replacement Study; HERS), treatment with daily CE 0.625 mg/MPA 2.5 mg demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year one, but not during the subsequent years. Two thousand three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in the HERS, the HERS II, and overall.

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. (See CLINICAL STUDIES.)

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). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. (See CLINICAL STUDIES.)

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 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 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

The most important randomized clinical trial providing information about this issue in estrogen alone users is the Women's Health Initiative (WHI) substudy of daily conjugated estrogens (CE 0.625 mg). In the estrogen alone substudy of WHI, after an average of 7.1 years of follow-up, daily CE 0.625 mg was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80, 95 percent nominal confidence interval [nCI] 0.62-1.04). (See CLINICAL STUDIES.)

The most important randomized clinical trial providing information about this issue in estrogenplus progestin users is the Women’s Health Initiative (WHI) substudy of daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg). In the estrogen plus progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE/MPA. In this substudy, prior use of estrogen alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24 (95 percent nCI 1.01-1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo, respectively. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups. (See CLINICAL STUDIES.)

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 Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily conjugated estogens (CE 0.625 mg) or placebo. In the estrogen plus progestin WHIMS substudy, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE 0.625 mg plus medroxyprogesterone acetate (MPA 2.5 mg) or placebo.

In the estrogen alone 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 substudy, after an average follow-up of 4 years, 40 women in the estrogen plus progestin group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen plus progestin 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.

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI 1.19-2.60). Since both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS 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 postmenopausal 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.

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 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. 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 1.58 (95 percent nCI 0.77-3.24). The absolute risk for CE/MPA 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 5 or more years, has been associated with an increased risk of ovarian cancer. 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 women with these conditions.

11. Barrier contraceptives

Premarin Vaginal Cream exposure has been reported to weaken latex condoms. The potential for Premarin Vaginal Cream to weaken and contribute to the failure of condoms, diaphragms, or cervical caps made of latex or rubber should be considered.

B. Patient Information

Physicians are advised to discuss the contents of the PATIENT INFORMATION leaflet with patients for whom they prescribe Premarin Vaginal Cream.

C. Laboratory Tests

Serum follicle stimulating hormone and estradiol levels have not been shown to be useful in the management of moderate to severe symptoms of vulvar and vaginal atrophy.

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 antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor 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) 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. 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 HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels.
  5. Impaired glucose tolerance.

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 breast, uterus, cervix, vagina, testis, and liver.

F. Pregnancy

Premarin Vaginal Cream should not be used during pregnancy. (See CONTRAINDICATIONS.)

G. Nursing Mothers

Premarin Vaginal Cream should not be used during lactation. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving the 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 adult 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

There have not been sufficient numbers of geriatric patients involved in studies utilizing Premarin Vaginal Cream to determine whether those over 65 years of age differ from younger subjects in their response to Premarin Vaginal Cream.

In the estrogen alone substudy of the Women's Health Initiative (WHI) study, 46 percent (n=4,943) were 65 years of age and older, while 7.1 percent (n=767) were 75 years of age and older. There was a higher relative risk (daily conjugated estrogens [CE 0.625 mg] versus placebo) of stroke in women less than 75 years of age compared to women 75 years of age and older.

In the estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women, 65 to 79 years of age, was randomized to daily CE 0.625 mg or placebo. After an average follow-up of 5.2 years, the relative risk (CE versus placebo) of probable dementia was 1.49 (95 percent CI 0.83-2.66). The absolute risk of developing probable dementia with estrogen alone was 37 versus 25 cases per 10,000 women-years compared with placebo.

Of the total number of subjects in the estrogen plus progestin substudy of the Women's Health Initiative study, 44 percent (n = 7,320) were 65 years of age and older, while 6.6 percent (n = 1,095) were 75 years and older. In women 75 years of age and older compared to women less than 74 years of age, there was a higher relative risk of nonfatal stroke and invasive breast cancer in the estrogen plus progestin group versus placebo. In women greater than 75, the increased risk of nonfatal stroke and invasive breast cancer observed in the estrogen plus progestin group compared to placebo was 75 versus 24 per 10,000 women-years and 52 versus 12 per 10,000 women-years, respectively.

In the estrogen plus progestin WHIMS substudy, a population of 4,532 postmenopausal women, 65 to 79 years of age, was randomized to daily CE 0.625 mg/MPA 2.5 mg or placebo. In the estrogen plus progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95 percent CI 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 versus 22 cases per 10,000 women-years compared with placebo.

Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE alone group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer’s disease.

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI 1.19-2.60). Since both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)

ADVERSE REACTIONS

See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.

Systemic absorption occurs with the use of Premarin Vaginal Cream. Warnings, precautions, and adverse reactions associated with oral Premarin treatment should be taken into account.

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

  1. Genitourinary system: Abnormal uterine bleeding/spotting; dysmenorrhea/pelvic pain; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in cervical secretion; change in amount of cervical ectropion; cystitis-like syndrome; application site reactions of vulvovaginal discomfort including burning and irritation; genital pruritus; ovarian cancer; endometrial hyperplasia; endometrial cancer.
  2. Breasts: Tenderness, pain, enlargement, discharge, galactorrhea; breast cancer; fibrocystic breast changes.
  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; pancreatitis; increased incidence of gallbladder disease; 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; pruritis; rash.
  6. Eyes: Retinal vascular thrombosis; intolerance to contact lenses.
  7. Central Nervous System: Headache; migraine; dizziness; nervousness; mood disturbances; irritability; mental depression; exacerbation of chorea; exacerbation of epilepsy; dementia; possible growth potentiation of benign meningioma.
  8. Miscellaneous: Increase or decrease in weight; glucose intolerance; aggravation of porphyria; edema; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia (preexisting condition); exacerbation of asthma; increased triglycerides; arthralgias; leg cramps.

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 Premarin therapy with institution of appropriate symptomatic care.

DOSAGE AND ADMINISTRATION

Use of Premarin Vaginal Cream, alone or in combination with a progestin, should be limited to 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 and 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.

Given cyclically for short-term use only:

For treatment of atrophic vaginitis, or kraurosis vulvae. The lowest dose that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Administration should be cyclic (three weeks on and one week off).

Usual Dosage Range:

½ to 2 g daily, intravaginally, depending on the severity of the condition.

Instructions For Use Of Gentle Measure® Applicator

  1. Remove cap from tube.
  2. Screw nozzle end of applicator onto tube.
  3. Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the prescribed dose. Use the marked stopping points on the applicator as a guideline to measure the correct dose.
  4. Unscrew applicator from tube.
  5. Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into vagina and press plunger downward to its original position.

To Cleanse: Pull plunger to remove it from barrel. Wash with mild soap and warm water.

DO NOT BOIL OR USE HOT WATER.

HOW SUPPLIED

Premarin® (conjugated estrogens) Vaginal Cream—Each gram contains 0.625 mg conjugated estrogens, USP.

Combination package: Each contains Net Wt. 1 ½ oz (42.5 g) tube with one plastic applicator calibrated in ½ g increments to a maximum of 2 g (NDC 0046-0872-93).

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

PATIENT INFORMATION

Premarin® (conjugated estrogens) Vaginal Cream

Read this PATIENT INFORMATION before you start using Premarin Vaginal Cream and read what you geteach time you refill your Premarin Vaginal Cream prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about Premarin® Vaginal Cream (an estrogen mixture)?

What is Premarin Vaginal Cream?

Premarin Vaginal Cream is a medicine that contains a mixture of estrogen hormones.

What is Premarin Vaginal Cream used for?

Premarin Vaginal Cream is used after menopause to:

Who should not use Premarin Vaginal Cream?

Do not start using Premarin Vaginal Cream if you:

Tell your healthcare provider:

How should I use Premarin Vaginal Cream?

The Gentle Measure® Applicator has been specifically designed for comfortable, easy use.

  1. Remove cap from tube.
  2. Screw nozzle end of applicator onto tube.
  3. Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the prescribed dose. Use the marked stopping points on the applicator as a guideline to measure the correct dose, as prescribed by your healthcare provider.
  4. Unscrew applicator from tube.
  5. Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into vagina and press plunger downward to its original position.

TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and warm water.

DO NOT BOIL OR USE HOT WATER.

Premarin Vaginal Cream should be used at the lowest possible dose for your treatment and only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with Premarin Vaginal Cream.

What are the possible side effects of Premarin Vaginal Cream?

Premarin Vaginal Cream is only used in and around the vagina. However, the risks associated with oral Premarin treatment should be taken into account.

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious but less common side effects include:

Some of the warning signs of these serious side effects include:

Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptoms that concern you.

Less serious but common side effects include:

These are not all the possible side effects of Premarin Vaginal Cream. For more information, ask your healthcare provider or pharmacist.

What can I do to lower my chances of getting a serious side effect with Premarin Vaginal Cream?

General information about the safe and effective use of Premarin Vaginal Cream

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Premarin Vaginal Cream for conditions for which it was not prescribed. Do not give Premarin Vaginal Cream to other people, even if they have the same symptoms you have. It may harm them. Keep Premarin Vaginal Cream out of the reach of children.

This leaflet provides a summary of the most important information about Premarin Vaginal Cream. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Premarin Vaginal Cream that is written for health professionals. You can get more information by calling the toll free number 1-800-934-5556.

What are the ingredients in Premarin Vaginal Cream?

Premarin Vaginal Cream contains a mixture of conjugated estrogens, which are a mixture of sodium estrone sulfate and sodium equilin sulfate and other components including sodium sulfate conjugates: 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. Premarin Vaginal Cream also contains cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin, and mineral oil.

Premarin® (conjugated estrogens) Vaginal Cream—Each gram contains 0.625 mg conjugated estrogens, USP.

Combination package: Each contains Net Wt. 1 ½ oz (42.5 g) tube with one plastic applicator calibrated in ½ g increments to a maximum of 2 g (NDC 0046-0872-93).

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Image from Drug Label ContentThis product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Image from Drug Label Content

Wyeth®

Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101

W10413C014
ET01
Rev 03/08

«TEAR HERE

PATIENT INFORMATION


Premarin® (conjugated estrogens)
Vaginal Cream in a nonliquefying base

Rx only

Read this PATIENT INFORMATION before you start using Premarin Vaginal Cream and read what you get each time you refill your Premarin Vaginal Cream prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about Premarin® (an estrogen mixture)?

What is Premarin Vaginal Cream?

Premarin Vaginal Cream is a medicine that contains a mixture of estrogen hormones.

What is Premarin Vaginal Cream used for?

Premarin Vaginal Cream is used after menopause to:

Who should not use Premarin Vaginal Cream?

Do not start using Premarin Vaginal Cream if you:

Tell your healthcare provider:

How should I use Premarin Vaginal Cream?

The Gentle Measure® Applicator has been specifically designed for comfortable, easy use.

  1. Remove cap from tube.
  2. Screw nozzle end of applicator onto tube.
  3. Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the prescribed dose. Use the marked stopping points on the applicator as a guideline to measure the correct dose, as prescribed by your healthcare provider.
  4. Unscrew applicator from tube.
  5. Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into vagina and press plunger downward to its original position.

TO CLEANSE: Pull plunger to remove it from barrel. Wash with mild soap and warm water.

DO NOT BOIL OR USE HOT WATER.

Premarin Vaginal Cream should be used at the lowest possible dose for your treatment and only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with Premarin Vaginal Cream.

What are the possible side effects of Premarin Vaginal Cream?

Premarin Vaginal Cream is only used in and around the vagina. However, the risks associated with oral Premarin treatment should be taken into account.

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious but less common side effects include:

Some of the warning signs of these serious side effects include:

Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptoms that concern you.

Less serious but common side effects include:

These are not all the possible side effects of Premarin Vaginal Cream. For more information, ask your healthcare provider or pharmacist.

What can I do to lower my chances of getting a serious side effect with Premarin Vaginal Cream?

General information about the safe and effective use of Premarin Vaginal Cream

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Premarin Vaginal Cream for conditions for which it was not prescribed. Do not give Premarin Vaginal Cream to other people, even if they have the same symptoms you have. It may harm them. Keep Premarin Vaginal Cream out of the reach of children.

This leaflet provides a summary of the most important information about Premarin Vaginal Cream. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Premarin Vaginal Cream that is written for health professionals. You can get more information by calling the toll free number 1-800-934-5556.

What are the ingredients in Premarin Vaginal Cream?

Premarin Vaginal Cream contains a mixture of conjugated estrogens, which are a mixture of sodium estrone sulfate and sodium equilin sulfate and other components including sodium sulfate conjugates: 17 α-dihydroequilin, 17 α-estradiol, and 17 β-dihydroequilin. Premarin Vaginal Cream also contains cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin, and mineral oil.

Premarin® (conjugated estrogens) Vaginal Cream—Each gram contains 0.625 mg conjugated estrogens, USP.

Combination package: Each contains Net Wt. 1 ½ oz (42.5 g) tube with one plastic applicator calibrated in ½ g increments to a maximum of 2 g (NDC 0046-0872-93).

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Image from Drug Label ContentThis product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. Image from Drug Label Content

Wyeth®

Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101

W10413C014
ET01
Rev 03/08


Premarin (Conjugated Estrogens)
PRODUCT INFO
Product Code0046-0872Dosage FormCREAM
Route Of AdministrationTOPICAL, VAGINALDEA Schedule
INGREDIENTS
Name (Active Moiety)TypeStrength
conjugated estrogens (conjugated estrogens) Active0.625 MILLIGRAM  In 1 GRAM
Glyceryl MonostearateInactive 
Cetyl Esters WaxInactive 
Cetyl AlcoholInactive 
Methyl StearateInactive 
GlycerinInactive 
White WaxInactive 
Propylene Glycol MonostearateInactive 
Benzyl AlcoholInactive 
Sodium Lauryl SulfateInactive 
Mineral OilInactive 
IMPRINT INFORMATION
CharacteristicAppearanceCharacteristicAppearance
ColorScore
ShapeSymbol
Imprint CodeCoating
Size
PACKAGING
#NDCPackage DescriptionMultilevel Packaging
10046-0872-9342.5 GRAM In 1 TUBE, WITH APPLICATORNone

Revised: 03/2008Wyeth Pharmaceuticals, Inc.