Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2082
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Premarin (Injection, Powder, Lyophilized, For Solution)
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For treatment of abnormal
uterine bleeding due to hormonal imbalance in the absence of organic
pathology: One 25 mg
injection, intravenously or intramuscularly. Intravenous use is preferred
since more rapid response can be expected from this mode of administration.
Repeat in 6 to 12 hours if necessary. The use of Premarin
Intravenous for injection does not preclude the advisability of other
appropriate measures. One should adhere to the usual precautionary measures governing intravenous
administration. Injection should be made SLOWLY to obviate the occurrence
of flushes. Infusion
of Premarin Intravenous for injection with other agents is not generally
recommended. In emergencies, however, when an infusion has already
been started it may be expedient to make the injection into the tubing
just distal to the infusion needle. If so used, compatibility of solutions
must be considered. COMPATIBILITY OF SOLUTIONS: Premarin Intravenous is compatible with
normal saline, dextrose, and invert sugar solutions. It is not compatible with protein hydrolysate, ascorbic
acid, or any solution with an acid pH.
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| dailymed-instance:descripti... |
Premarin Intravenous (conjugated estrogens, USP) for injection 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 materials 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��-dihydroequilin, 17��-estradiol,
and 17��-dihydroequilin. Each Secule vial contains 25 mg of conjugated
estrogens, USP, in a sterile lyophilized cake which also contains
lactose 200 mg, sodium citrate 12.2 mg, and simethicone
0.2 mg. The pH is adjusted with sodium hydroxide or hydrochloric
acid. The reconstituted solution is suitable for intravenous or intramuscular
injection.
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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 innormally 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.<br/>Pharmacokinetics:<br/>A. Absorption: Conjugated
estrogens are water-soluble and are well-absorbed through the skin,
mucous membranes, and gastrointestinal tract after release from the
drug formulation.<br/>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.<br/>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 proportion of the circulating estrogens exists
as sulfate conjugates, especially estrone sulfate, which serves as
a circulating reservoir for the formation of more active estrogens.<br/>D. Excretion: Estradiol,
estrone, and estriol are excreted in the urine, along with glucuronide
and sulfate conjugates.<br/>E. Special Populations: No pharmacokinetic
studies were conducted in special populations, including patients
with renal or hepatic impairment.<br/>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.
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Premarin Intravenous therapy
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 (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 Intravenous
for injection. 8. Known
or suspected pregnancy.
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| dailymed-instance:supply |
NDC 0046-0749-05���Each
package provides one SECULE vial containing
25 mg of conjugated estrogens, USP, for injection (also lactose
200 mg, sodium citrate 12.2 mg, and simethicone 0.2 mg).
The pH is adjusted with sodium hydroxide or hydrochloric acid. Premarin Intravenous (conjugated estrogens,
USP) for injection is prepared by cryodesiccation. SECULE-Registered trademark to designate a vial
containing an injectable preparation in dry form.
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WARNINGS:<br/>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.)<br/>CARDIOVASCULAR AND OTHER RISKS: Estrogens with or
without progestins should not be used for the prevention of cardiovascular
disease or dementia. The estrogen alone substudy of the 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 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.
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A. General: Premarin Intravenous
for injection is indicated for short-term use. However, warnings,
precautions and adverse reactions associated with oral Premarin treatment
should be taken into account.<br/>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 which 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.<br/>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.<br/>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.<br/>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.<br/>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 Tand Tserum 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.<br/>6. Fluid retention: 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.<br/>7. Hypocalcemia: Estrogens
should be used with caution in individuals with severe hypocalcemia.<br/>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.<br/>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.<br/>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.<br/>B. Patient Information: Physicians are advised
to discuss the contents of the PATIENT INFORMATION leaflet with
patients who are being treated with Premarin Intravenous.<br/>C. Laboratory Tests: Estrogen administration
should be guided by clinical response at the lowest dose, rather than
laboratory monitoring.<br/>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 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) leading to increased
circulating total thyroid hormone, as measured by protein-bound iodine
(PBI), Tlevels (by column or by radioimmunoassay) or
Tlevels by radioimmunoassay. Tresin uptake
is decreased, reflecting the elevated TBG. Free Tand
free Tconcentrations 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 HDLsubfraction concentrations,
reduced LDL cholesterol concentration, increased triglyceride levels. 5. Impaired glucose tolerance.<br/>E. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term continuous administration of natural and synthetic estrogens
in certain animal species increases the frequency of carcinomas of
the breast, uterus, cervix, vagina, testis, and liver.<br/>F. Pregnancy: Premarin Intravenous
should not be used during pregnancy.<br/>G. Nursing Mothers: Premarin Intravenous
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.<br/>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.<br/>I. Geriatric Use: There have not been
sufficient numbers of geriatric patients involved in studies utilizing
Premarin to determine whether those over 65 years of age differ from
younger subjects in their response to Premarin. 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.
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| dailymed-instance:overdosag... |
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.
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| dailymed-instance:genericMe... |
Conjugated Estrogens
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| dailymed-instance:fullName |
Premarin (Injection, Powder, Lyophilized, For Solution)
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| dailymed-instance:adverseRe... |
See BOXED WARNINGS, WARNINGS, and PRECAUTIONS. Premarin
Intravenous for injection is indicated for short-term use. However,
the 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.<br/>1. Genitourinary system.:<br/>2. Breasts.:<br/>3. Cardiovascular.:<br/>4. Gastrointestinal.:<br/>5. Skin.:<br/>6. Eyes.:<br/>7. Central Nervous System.:<br/>8. Miscellaneous.:
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| dailymed-instance: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.)<br/>CARDIOVASCULAR AND OTHER RISKS: Estrogens with or
without progestins should not be used for the prevention of cardiovascular
disease or dementia. The estrogen alone substudy of the 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 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.
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| dailymed-instance:indicatio... |
Premarin Intravenous (conjugated
estrogens, USP) for injection is indicated in the treatment of abnormal
uterine bleeding due to hormonal imbalance in the absence of organic
pathology. Premarin
Intravenous is indicated for short-term use only, to provide a rapid
and temporary increase in estrogen levels.
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| dailymed-instance:name |
Premarin
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