Premarin - Conjugated Estrogens injection, Powder, Lyophilized, For Solution prescribing information
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER and PROBABLE DEMENTIA
Estrogen-Alone Therapy
Endometrial Cancer
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. (See WARNINGS, Malignant Neoplasms, Endometrial cancer .)
Cardiovascular Disorders and Probable Dementia
Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Probable Dementia .)
The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders .)
The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the 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, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Probable 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 other dosage forms of estrogens.
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.
Estrogen Plus Progestin Therapy
Cardiovascular Disorders and Probable Dementia
Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Probable Dementia .)
The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders .)
The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older 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, Probable Dementia and PRECAUTIONS, Geriatric Use .)
Breast Cancer
The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer. (See CLINICAL STUDIES and WARNINGS, Malignant Neoplasms, Breast cancer .)
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.
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.
INDICATIONS AND USAGE
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.
DOSAGE AND ADMINISTRATION
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.
CONTRAINDICATIONS
Premarin Intravenous therapy should not be used in individuals with any of the following conditions:
- Undiagnosed abnormal genital bleeding.
- Known, suspected, or history of breast cancer.
- Known or suspected estrogen-dependent neoplasia.
- Active DVT, PE or a history of these conditions.
- Active arterial thromboembolic disease (for example, stroke and MI) or a history of these conditions.
- Known anaphylactic reaction and angioedema to Premarin Intravenous therapy.
- Known liver dysfunction or disease.
- Known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders.
- Known or suspected pregnancy.
ADVERSE REACTIONS
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 identified during post-approval use of oral or intravenous Premarin. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Genitourinary system
- Abnormal uterine bleeding/spotting.
- Dysmenorrhea or pelvic pain.
- Increase in size of uterine leiomyomata.
- Vaginitis, including vaginal candidiasis.
- Change in amount of cervical secretion.
- Change in cervical ectropion.
- Ovarian cancer.
- Endometrial hyperplasia.
- Endometrial cancer.
Breasts
- Tenderness, enlargement, pain, discharge, galactorrhea.
- Fibrocystic breast changes.
- Breast cancer.
Cardiovascular
- Deep and superficial venous thrombosis.
- Pulmonary embolism.
- Thrombophlebitis.
- Myocardial infarction.
- Stroke.
- Increase in blood pressure.
Gastrointestinal
- Nausea, vomiting.
- Abdominal cramps, bloating.
- Cholestatic jaundice.
- Increased incidence of gallbladder disease.
- Pancreatitis.
- Enlargement of hepatic hemangiomas.
- Ischemic colitis.
Skin
- Chloasma or melasma that may persist when drug is discontinued.
- Erythema multiforme.
- Erythema nodosum.
- Hemorrhagic eruption.
- Loss of scalp hair.
- Hirsutism.
- Pruritis.
- Rash.
Eyes
- Retinal vascular thrombosis.
- Intolerance to contact lenses.
Central Nervous System
- Headache.
- Migraine.
- Dizziness.
- Mental depression.
- Exacerbation of chorea.
- Nervousness.
- Exacerbation of epilepsy.
- Dementia.
- Possible growth potentiation of benign meningioma.
Miscellaneous
- Increase or decrease in weight.
- Glucose intolerance.
- Aggravation of porphyria.
- Edema.
- Arthralgia.
- Leg cramps.
- Changes in libido.
- Urticaria.
- Hypocalcemia (preexisting condition).
- Injection site pain.
- Injection site edema.
- Phlebitis (injection site).
- Exacerbation of asthma.
- Increased triglycerides.
DESCRIPTION
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, 17α-dihydroequilin, 17α-estradiol, and 17β-dihydroequilin.
Each single-dose vial contains 25 mg/vial 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.
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 in the 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 gastrointestinal tract after release from the drug formulation.
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 a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
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 CE and MPA 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 (Hypericum perforatum) preparations, 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 daily oral CE (0.625 mg)-alone or in combination with 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) defined as nonfatal 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, PE, endometrial cancer (only in CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These studies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.
WHI Estrogen-Alone Substudy
The WHI 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 63 years of age, 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 7.1 years, are presented in Table 1.
| Event | Relative Risk CE vs. Placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) | CE n = 5,310 | Placebo n = 5,429 |
|---|---|---|---|
| Absolute Risk per 10,000 Women-Years | |||
CHD events Results are based on centrally adjudicated data for an average follow-up of 7.1 years. | 0.95 (0.78–1.16) | 54 | 57 |
Non-fatal MI | 0.91 (0.73–1.14) | 40 | 43 |
CHD death | 1.01 (0.71–1.43) | 16 | 16 |
All Stroke | 1.33 (1.05–1.68) | 45 | 33 |
Ischemic stroke | 1.55 (1.19–2.01) | 38 | 25 |
Deep vein thrombosis , Not included in Global Index. | 1.47 (1.06–2.06) | 23 | 15 |
Pulmonary embolism | 1.37 (0.90–2.07) | 14 | 10 |
Invasive breast cancer | 0.80 (0.62–1.04) | 28 | 34 |
Colorectal cancer Results are based on an average follow-up of 6.8 years. | 1.08 (0.75–1.55) | 17 | 16 |
Hip fracture | 0.65 (0.45–0.94) | 12 | 19 |
Vertebral fractures , | 0.64 (0.44–0.93) | 11 | 18 |
Lower arm/wrist fractures , | 0.58 (0.47–0.72) | 35 | 59 |
Total fractures , | 0.71 (0.64–0.80) | 144 | 197 |
Death due to other causes , All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. | 1.08 (0.88–1.32) | 53 | 50 |
Overall mortality , | 1.04 (0.88–1.22) | 79 | 75 |
Global Index A 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. | 1.02 (0.92–1.13) | 206 | 201 |
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 7 fewer hip fractures. The absolute excess risk of events included in the "global index" was a nonsignificant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.
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 was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years.
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 of ischemic stroke, and this excess was present in all subgroups of women examined.
Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36–1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46–1.11)].
WHI Estrogen Plus Progestin Substudy
The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive 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.
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 plus MPA were 7 more CHD events, 8 more strokes, 10 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. Results of the estrogen plus progestin substudy, which included 16,608 women (average 63 years of age, 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.
| Event | Relative Risk CE/MPA vs. Placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) | CE/MPA n = 8,506 | Placebo n = 8,102 |
|---|---|---|---|
| Absolute Risk per 10,000 Women-Years | |||
CHD events | 1.23 (0.99–1.53) | 41 | 34 |
Non-fatal MI | 1.28 (1.00–1.63) | 31 | 25 |
CHD death | 1.10 (0.70–1.75) | 8 | 8 |
All Strokes | 1.31 (1.03–1.68) | 33 | 25 |
Ischemic Stroke | 1.44 (1.09–1.90) | 26 | 18 |
Deep vein thrombosis Not included in "global index". | 1.95 (1.43–2.67) | 26 | 13 |
Pulmonary embolism | 2.13 (1.45–3.11) | 18 | 8 |
Invasive breast cancer Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. | 1.24 (1.01–1.54) | 41 | 33 |
Colorectal cancer | 0.61 (0.42–0.87) | 10 | 16 |
Endometrial cancer | 0.81 (0.48–1.36) | 6 | 7 |
Cervical cancer | 1.44 (0.47–4.42) | 2 | 1 |
Hip fracture | 0.67 (0.47–0.96) | 11 | 16 |
Vertebral fractures | 0.65 (0.46–0.92) | 11 | 17 |
Lower arm/wrist fractures | 0.71 (0.59–0.85) | 44 | 62 |
Total fractures | 0.76 (0.69–0.83) | 152 | 199 |
Overall mortality All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. | 1.00 (0.83–1.19) | 52 | 52 |
Global Index A 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. | 1.13 (1.02–1.25) | 184 | 165 |
Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44–1.07)].
Women's Health Initiative Memory Study
The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 5.2 years, 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. Probable dementia as defined in this study included Alzheimer disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use .)
The WHIMS estrogen plus progestin ancillary study enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable 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 percent 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 WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use .)
HOW SUPPLIED
NDC 0046-0749-05–Each package provides one single-dose vial containing 25 mg/vial 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.
