Consumer Drug Information File (DEC. 1990)
Monograph Title: ESTROGEN Pronunciation: ess' troe jen
Synonyms: conjugated estrogens; Estinyl; Estrace; Estraderm; estradiol; ethinyl estradiol; Premarin; others
WHY is this drug prescribed?
Estrogen is a hormone, a substance produced by the body. It is needed for normal growth and development of female sex organs and for natural functions such as bearing children. Estrogen is used to relieve feelings of warmth in the face, neck, and chest, "hot flashes", and sweating that occur during menopause (when your estrogen production declines). It also is used for conditions caused by insufficient estrogen (after menopause or due to other medical problems), including dry, itchy external genitals and vaginal irritation. It also is prescribed for young women who do not mature physically at the usual rate, for breast and prostate cancer, and to dry up breast milk after the birth of a baby. Estrogen also is used with diet, calcium supplements, and exercise to slow the progression of osteoporosis, a disease (common in women after menopause) resulting in bones that break easily. DESCRIPTORS: Use
WHEN should it be used?
Estrogen usually is taken on a cyclical basis once a day for 21 days and then none for seven days, then the cycle is repeated. However, for cancer it usually is taken three times a day continuously for at least three months. Follow the instructions on your prescription label carefully, and ask your doctor or pharmacist to explain any part that you do not understand. DESCRIPTORS: Dosage; Instructions
HOW should it be used?
Estrogen comes in tablets, skin patches, vaginal cream, and injection form. Your prescription label tells you how much to take at each dose. Skin patches usually are applied twice weekly for three weeks (on the same two days each week), followed by one week without the drug, then the cycle is repeated. The package is specially designed to help you remember when to apply fresh skin patches. To apply a skin patch, follow the instructions provided and these steps 1. Remove the skin patch from its protective pouch and peel off the protective strip, exposing the adhesive surface. 2. Place the adhesive side against a clean, dry, and not excessively hairy area of skin on the trunk of your body, preferably your abdomen (not your waistline, since tight clothing may rub the patch off, or breasts). Do not apply the patch to oily, broken, or irritated skin. 3. Press the patch firmly with the palm of your hand for about 10 seconds, making sure that the edges adhere to your skin. If the patch accidentally comes off, you can either reapply it or apply a fresh patch, but follow your regular dosing schedule. Remove and discard the patch and apply a fresh patch according to the schedule prescribed by your doctor. To prevent skin irritation, use a different site for each application and wait at least one week before using a particular site again. Follow the instructions that come with the vaginal cream. Ask your doctor or pharmacist any questions you have about using it. You may wish to wear a sanitary napkin after inserting the cream to keep your clothes clean. If you use the vaginal cream once a day, it is best to use it at bedtime. Ask your doctor or pharmacist any questions you have about refilling your prescription. DESCRIPTORS: Administration; Instructions
What SPECIAL INSTRUCTIONS should I follow while using this drug?
Ask your doctor or pharmacist for a copy of the manufacturer's information for the patient. Keep all appointments for checkups so that your doctor can evaluate your response to the drug. You should have a complete physical examination annually (including a Pap test to detect vaginal cancer in women). Ask your doctor to teach you how to examine your breasts, report any lumps immediately. DESCRIPTORS: Instructions
What should I do IF I FORGET to take a dose?
If you forget to apply a skin patch, apply it as soon as you remember, note the date on the package, and adjust your schedule. If you miss a dose of tablets or vaginal cream, take it as soon as you remember. However, if you remember a missed dose near the time you are scheduled to take the next dose, take only the regularly scheduled dose. Do not take a double dose. DESCRIPTORS: Dosage; Instructions
Side Effects
Nausea, vomiting, cramps, bloating, diarrhea, appetite and weight changes. Eat a light snack if you experience nausea. If these effects persist or are severe, contact your doctor. Brown or black skin patches, swelling of hands, feet, or lower legs (fluid retention), bleeding or spotting between menstrual periods, changes in menstrual flow, painful or missed menstrual periods, breast tenderness, enlargement, or secretion, intolerance to contact lenses. Contact your doctor if these effects are bothersome. Skin redness and irritation (from skin patches). Use a different site for each application. If these effects are severe or persist for more than a day, contact your doctor. Sudden, severe headache or vomiting, vision or speech problems, sudden partial or complete loss of vision, dizziness or faintness, weakness or numbness of an arm or leg, sharp, crushing chest pain or heaviness in chest, cough, coughing up of blood, sudden shortness of breath, calf pain, severe abdominal pain, yellowing of skin or eyes, itching, and loss of appetite, severe mental depression, unusual bleeding. Contact your doctor immediately. DESCRIPTORS: Cautions
Precautions
Before you take estrogen, tell your doctor your entire medical history, including family medical history, especially breast lumps or cancer, high blood pressure, diabetes, asthma, epilepsy (seizures), migraine headaches, liver, heart, or kidney disease, mental depression, toxemia (high blood pressure during pregnancy), jaundice (yellowing of skin or eyes) during pregnancy, and excessive weight gain and fluid retention (bloating) during the menstrual cycle. Tell your doctor if you are allergic to aspirin or tartrazine (a yellow dye in some processed foods and medications, including estrogen). Estrogen may affect the way your body responds to certain other drugs. Tell your doctor what prescription and nonprescription medications you are taking. Before having surgery, tell the doctor that you take estrogen. Before you have any laboratory tests, tell the laboratory personnel and doctor that you take estrogen. Before you take estrogen, tell your doctor if you are pregnant or breast-feeding. Estrogen can harm an unborn baby. If you become pregnant while taking estrogen, stop taking it and contact your doctor promptly. Do not allow anyone else to take this medication. DESCRIPTORS: Cautions; Interactions
Storing Your Medication
Keep this medication in the container it came in, tightly closed, and out of the reach of children. Store it at room temperature. Do not remove skin patches from their protective pouches until just before applying them. DESCRIPTORS: Storage
Copr., 1991, Am. Soc. of Hospital Pharmacists, Inc. All Rights Reserved.
DRUG INFORMATION FULLTEXT - OCT 1990
(COPR. ASHP 1990)
AHFS NO: 68.16 AHFS CLASS: Estrogens SUBFILE: HANDBOOK ON INJECTABLE DRUGS MONOGRAPH TITLE: Estrogens, Conjugated GENERIC NAME: ESTROGENS, CONJUGATED TRADE NAME(S): Premarin Intravenous Wyeth-Ayerst PRODUCTS (PD): PRIMARY TEXT:
[5305,5315] Estrogens, conjugated (Wyeth-Ayerst), is available in packages containing a vial with lyophilized estrogens, conjugated, 25 mg; lactose 200 mg; sodium citrate 12.5 mg; simethicone 0.2 mg; and sodium hydroxide or hydrochloric acid for pH adjustment. Also in the package is a 5-ml ampul of sterile diluent composed of water for injection and benzyl alcohol 2%. [5455] To constitute, withdraw the air from the vial of estrogens, conjugated; flow the sterile diluent slowly against the side of the vial, and agitate gently--not violently (2). pH [5155] The pH is adjusted to 7.2 (1-10/74).
CHEMISTRY AND STABILITY (CH): PRIMARY TEXT: [5345] The manufacturer recommends refrigeration of the intact containers at 2 to 8 DGC (2). Such storage provides a shelflife of up to 60 months. At room temperature, the product in intact vials is stable for 24 months (853). The constituted solution should be stored at 2 to 8 DGC (2). The constituted drug is stable for 60 days. Do not use it, however, if precipitation or discoloration occurs (2).
DOSAGE AND ADMINISTRATION (DO): PRIMARY TEXT: [5575] Administration may be made by deep intramuscular injection or direct intravenous injection. [5575,5605] Direct intravenous injection should be performed slowly to obviate flushing. [5575] Intravenous infusion is not recommended, but injection into the tubing of a running infusion may be expedient (2; 4; 8).
[5525] The dosage of estrogens, conjugated, must be individualized to the patient's condition, tolerance, and response. The lowest effective dosage should be used; therapy should be discontinued as soon as possible, if indicated (4). The usual dose is 25 mg, repeated in six to 12 hours if needed. [5555] Safe and effective use in children has not been established (2; 4).
COMPATIBILITY INFORMATION (CI):
SEE TABLE FORMAT OF THIS RECORD. Solutions
[5335] Dextrose, saline, and invert sugar solutions have been stated to be compatible with estrogens, conjugated (2).
Additives
[5365] Estrogens, conjugated, has been stated to be incompatible with ascorbic acid or any solution with an acid pH (2; 4).
REFERENCES (RF):
For a list of references cited in the text of this monograph, search the monograph titled HID References.
TABLES: --------------------------------------------------------------------- [5352] Y-Site Injection Compatibility (1:1 Mixture)
Estrogens, conjugated
DRUG (IN SYRINGE) MFR AMT MFR AMT REMARKS REF C I Heparin sodium RI 1000 AY 5 mg/ Physically compatible 322 C with units + ml for at least 4 hr at hydrocortisone 100 mg/ room temperature by sodium succinate La visual and microscopic examination Potassium chloride 40 mEq/ AY 5 mg/ Physically compatible 322 C La ml for at least 4 hr at room temperature by visual and microscopic examination Vitamin B complex RC 2 ml/La AY 5 mg/ Physically compatible 322 C with C ml for at least 4 hr at room temperature by visual and microscopic examination aTested in dextrose 5% in water, sodium chloride 0.9%, and Ringer's injection, lactated.
DESCRIPTORS: [5155] pH; [5305] Stability; [5315] Expiration date; [5455] Reconstitution mixing; [5525] Dosage schedule; [5555] Age dosage relation; [5575] Administration route; [5605] Adverse reaction (side effect); [5345] Storage; [5352] Equipment compatibility (Table); [5335] Vehicle compatibility; [5365] Additive compatibility
AHFS NO: 68.16 AHFS CLASS: ESTROGENS SUBFILE: American Hospital Formulary Service MONOGRAPH TITLE: Estrogens, Conjugated GENERIC NAME: Estrogens, Conjugated SYNONYMS: Estrogenic Substances, Conjugated TRADE NAME(S): Premarin Cycle Pack Wyeth-Ayerst/ Premarin Intravenous Wyeth-Ayerst/ Premarin Wyeth-Ayerst/ PMB 200 Wyeth-Ayerst/ Milprem-400 Wallace/ PMB 400 Wyeth-Ayerst/ Premarin with Methyltestosterone Wyeth-Ayerst
CHEMISTRY AND STABILITY (CH): PRIMARY TEXT: CHEMISTRY
[3115] Conjugated estrogens is a mixture containing the sodium salts of the water-soluble sulfate esters of estrone and equilin.
STABILITY
[3345] Commercially available conjugated estrogens tablets should be stored in well-closed containers. Conjugated estrogens tablets and vaginal cream should be stored at a temperature less than 40DGC, preferably between 15-30DGC; freezing of the vaginal cream should be avoided. Conjugated estrogens powder for injection should be stored at a temperature of 2-8DGC prior to reconstitution. [3345,3303] Following reconstitution, solutions of the drug are stable for up to 60 days when stored at 2-8DGC; however, solutions should not be used if they darken or if a precipitate is present.
ADDITIONAL TEXT: CHEMISTRY AND STABILITY CHEMISTRY
[3103] Conjugated estrogens may be derived wholly or in part from equine urine or may be prepared synthetically from estrone and equilin. [3113] Conjugated estrogens may also contain conjugated estrogenic substances of the type excreted by pregnant mares including 17-alpha-dihydroequilin, 17-alpha-estradiol, equilenin, and 17-alpha-dihydroequilenin. Conjugated estrogens contains 50-63% sodium estrone sulfate and 22.5-32.5% sodium equilin sulfate.
[3133] Conjugated estrogens obtained from natural sources occurs as a buff-colored, amorphous powder and is odorless or has a slight, characteristic odor. Conjugated estrogens that is prepared synthetically occurs as a white to light buff, crystalline or amorphous powder and is odorless or has a slight odor. [3143] Conjugated estrogens is soluble in water. [3113] Conjugated estrogens injection is commercially available as a sterile, lyophilized cake. [3413,3113] The lyophilized cake also contains lactose, sodium citrate, and simethicone; in addition, sodium hydroxide and/or hydrochloric acid may be added during manufacture of the powder for injection to adjust the pH. A sterile diluent containing water for injection and benzyl alcohol as a preservative is provided for reconstitution.
STABILITY
[3333,3323] Conjugated estrogens injection is physically and chemically compatible with the following IV solutions: 5% dextrose, 0.9% sodium chloride, and invert sugar solutions; the injection is physically and/or chemically incompatible with ascorbic acid or any solution with an acid pH. Specialized references should be consulted for specific compatibility information.
PHARMACOLOGY (PC): PRIMARY TEXT:
[3205] The principal pharmacologic effects of conjugated estrogens are similar to those of other natural and synthetic estrogens. (See Pharmacology in the Estrogens General Statement 68:16.)
USES (US): PRIMARY TEXT:
[3225,3643] In females, oral conjugated estrogens is used for the management of moderate to severe vasomotor symptoms associated with menopause; however, estrogens do not appear to be effective for the management of nervous symptoms or depression associated with menopause in patients without vasomotor symptoms, and the drugs should not be used in the management of such conditions in these patients. [3225] Oral conjugated estrogens is also used for the management of atrophic vaginitis, kraurosis vulvae, female hypogonadism and castration, and primary ovarian failure.
[3225,3003,3900] Oral conjugated estrogens may be used adjunctively with other therapeutic measures (e.g., diet, calcium, physical therapy) to retard further bone loss and the progression of osteoporosis associated with estrogen deficiency in postmenopausal women with evidence of bone loss or deficiency of bone mass. (100,101) (See Uses in the Estrogens General Statement 68:16.) [3225,3003] Estrogen replacement therapy has been shown to reduce bone resorption and retard or halt bone loss in postmenopausal women; (100) however, there is no clear method for identifying those women who will develop osteoporotic fractures, and there is a lack of substantial evidence that estrogen replacement therapy decreases the incidence of osteoporotic bone fractures. (101) Additional study is needed to determine the exact role and optimum regimen of estrogen and/or other modalities in the prevention of primary osteoporosis. (100)
[3225] Oral conjugated estrogens is used for the palliative treatment of advanced, inoperable, metastatic carcinoma of the breast in postmenopausal women and in men. However, because tamoxifen appears to be at least as effective as estrogen therapy in postmenopausal women and causes a lower incidence of severe adverse effects, tamoxifen is preferred by some clinicians.
[3225,3643] In males, oral conjugated estrogens is used for the palliative treatment of advanced, inoperable carcinoma of the prostate; however, the risk of adverse cardiovascular effects of estrogens must be considered.
[3225] Conjugated estrogens may be administered IM or IV for the treatment of abnormal uterine bleeding caused by hormonal imbalance not associated with organic pathology.
Conjugated estrogens may be administered intravaginally for the management of atrophic vaginitis or kraurosis vulvae.
[3225,3643,3653,3900] Conjugated estrogens has not been shown to be effective for any purpose during pregnancy, and use of the drug in pregnant women may cause severe harm to the fetus. (See Cautions: Pregnancy and Lactation, in the Estrogens General Statement 68:16.)
ADDITIONAL TEXT: USES
[3223] Although oral conjugated estrogens has been used for the prevention of postpartum breast engorgement, data from controlled studies indicate that the incidence of substantial painful engorgement is low in untreated women, and the condition usually responds to appropriate analgesic or other supportive therapy. [3223,3643] The benefit derived from estrogen therapy in the prevention of postpartum breast engorgement must be carefully weighed against the potential increased risk of puerperal thromboembolism associated with the use of large doses of estrogens. (See Cautions: Cardiovascular Effects, in the Estrogens General Statement 68:16.)
[3223,3643] Estrogens are not used in the treatment of breast cancer in premenopausal women because the drugs may potentially stimulate tumor growth rather than inhibit it.
[3223] The specific role of estrogen therapy compared with other therapies (e.g., chemotherapy, orchiectomy) in the treatment of prostatic cancer has not been clearly determined, and patients should generally be referred to physicians who are actively engaged in the investigation of the disease and are therefore familiar with the latest and most advantageous forms of therapy. Estrogen therapy is currently considered a therapy of choice for patients with inoperable prostatic tumors, for patients who refuse orchiectomy, and for patients whose disease progresses despite orchiectomy in whom the benefits of estrogen use are considered to outweigh the risk of adverse effects.
CAUTIONS (CA): PRIMARY TEXT:
[3605,3643,3900] Conjugated estrogens shares the toxic potentials of other estrogens, and the usual cautions, precautions, and contraindications associated with estrogen therapy should be observed. (See Cautions in the Estrogens General Statement 68:16.)
DOSAGE AND ADMINISTRATION (DO): PRIMARY TEXT: RECONSTITUTION AND ADMINISTRATION
[3575] Conjugated estrogens is usually administered orally, but may also be administered intravaginally, topically, or by deep IM or slow IV injection. When parenteral administration of conjugated estrogens is required, IV injection is preferred because of the more rapid response obtained following this route of administration compared to IM injection. For direct IV injection, the drug should be administered slowly to avoid the occurrence of a flushing reaction.
[3455] For parenteral administration, conjugated estrogens powder for injection is reconstituted with 5 mL of the diluent provided (sterile water for injection containing benzyl alcohol).
DOSAGE
[3525] Dosage of conjugated estrogens must be individualized according to the condition being treated and the tolerance and therapeutic response of the patient. To minimize the risk of adverse effects, the lowest possible effective dosage should be used. When short-term estrogen therapy is indicated (e.g., for the management of vasomotor symptoms associated with menopause; atrophic vaginitis; kraurosis vulvae), therapy should be discontinued as soon as possible; attempts to reduce dosage or discontinue the drug should be made at 3- to 6-month intervals.
Estrogen therapy is usually administered cyclically. The drugs are usually given once daily for 3 weeks, followed by 1 week without the drugs, and then this regimen is repeated as necessary.
DOSAGE [3526] Vasomotor Symptoms, Atrophic Vaginitis, and is Vulvae
[3525] For the management of moderate to severe vasomotor symptoms associated with menopause or for the management of atrophic vaginitis or kraurosis vulvae, the usual oral dosage of conjugated estrogens is 0.3-1.25 mg daily in a cyclic regimen; higher dosages may be required in some patients. The drug is usually administered once daily for 21 consecutive days, followed by 7 days without the drug, and then this regimen is repeated as necessary. If conjugated estrogens is used in the management of vasomotor symptoms and the woman is menstruating, administration of the drug is started on the fifth day of the menstrual cycle; if the woman has not menstruated within the last 2 or more months prior to initiation of conjugated estrogens therapy, administration of the drug is started arbitrarily. Alternatively, for the management of atrophic vaginitis or kraurosis vulvae, 2-4 g of conjugated estrogens vaginal cream may be administered intravaginally or topically once daily in the usual cyclic regimen.
DOSAGE [3526] Female Hypogonadism
[3525] For replacement therapy in female hypogonadism, the usual oral dosage of conjugated estrogens is 2.5-7.5 mg daily given in divided doses for 20 consecutive days, followed by 10 days without the drug. If menstruation does not occur by the end of this period, the same dosage schedule should be repeated. The number of courses of estrogen therapy required to induce menstruation varies, depending on the individual responsiveness of the endometrium. If menstruation occurs before the end of the 10-day drug-free period, a 20-day estrogen-progestin regimen should be initiated with conjugated estrogens 2.5-7.5 mg daily given in divided doses for 20 days; during the last 5 days of estrogen therapy, an oral progestin is administered. If menstruation begins before this estrogen-progestin regimen is completed, therapy should be discontinued and then reinstituted on the fifth day of menstruation.
DOSAGE [3526] Female Castration, Primary Ovarian Failure, and rosis
[3525] For the management of female castration or primary ovarian failure, or for the adjunctive treatment of osteoporosis, the usual initial oral dosage of conjugated estrogens is 1.25 mg daily in a cyclic regimen. To retard further bone loss and the progression of osteoporosis associated with estrogen deficiency in postmenopausal women with evidence of bone loss or deficiency of bone mass, the usual oral dosage of conjugated estrogens is 0.625 mg daily in a cyclic regimen. (101) The drug is usually administered once daily for 21 consecutive days followed by 7 days without the drug, and then this regimen is repeated as necessary. Subsequent dosage should be adjusted according to the severity of the symptoms and the patient's therapeutic response, using the lowest possible effective maintenance dosage.
DOSAGE [3526] Postpartum Breast Engorgement
[3525] For the prevention of postpartum breast engorgement, the usual oral dosage of conjugated estrogens is 3.75 mg every 4 hours for 5 doses, or 1.25 mg every 4 hours for 5 days.
DOSAGE [3526] Inoperable Carcinoma of the Breast
[3525] For the palliative treatment of inoperable, advanced, metastatic carcinoma of the breast in appropriately selected men and postmenopausal women, the usual oral dosage of conjugated estrogens is 10 mg 3 times daily. Estrogen therapy is usually continued in these patients for at least 3 months.
DOSAGE [3526] Inoperable Carcinoma of the Prostate
[3525] For the palliative treatment of inoperable, advanced carcinoma of the prostate, the usual oral dosage of conjugated estrogens is 1.25-2.5 mg 3 times daily. Efficacy of estrogen therapy in these patients can be evaluated according to the patient's symptomatic improvement and by serial determinations of serum acid phosphatase concentration. In general, if a response to conjugated estrogens therapy is going to occur, it should be apparent within 3 months following initiation of therapy. If a response does occur, conjugated estrogens therapy should be continued until substantial progression of the disease occurs.
DOSAGE [3526] Abnormal Uterine Bleeding
[3525] For the emergency treatment of abnormal uterine bleeding caused by hormonal imbalance, the usual IV or IM dose of conjugated estrogens is 25 mg. If necessary, the dose may be repeated in 6-12 hours. The use of conjugated estrogens for this condition does not preclude the use of other appropriate measures.
ADDITIONAL TEXT: DOSAGE AND ADMINISTRATION RECONSTITUTION AND ADMINISTRATION
[3453] To facilitate introduction of the diluent, at least 5 mL of air should initially be withdrawn from the vial (Secule) containing the powder for injection. Using aseptic technique, the diluent should then be slowly added, directing the flow against the inner wall of the Secule, while gently agitating the container to facilitate dissolution of the contents; vigorous shaking of the container should be avoided.
DOSAGE
[3523,3003,3683] Addition of progestin therapy for 7 or more days of a cycle of estrogen administration has been associated with a decreased incidence of endometrial hyperplasia. Morphologic and biochemical studies of the endometrium suggest that 10-13 days of progestin are needed to provide maximum maturation of the endometrium and to eliminate any hyperplastic changes. [3523,3003,3643,3663] It has not been clearly established whether addition of progestin therapy will reduce the risk of developing endometrial carcinoma. [3003,3643,3523] When a progestin is used in conjunction with cyclic estrogen administration, the usual precautions associated with progestin therapy should be observed. Clinicians prescribing progestins should be aware of the risks associated with these drugs and the manufacturers' labeling should be consulted. The choice and dosage of a progestin may be important factors in minimizing potential adverse effects.
DOSAGE [3526] Abnormal Uterine Bleeding
[3900] For further information on chemistry, pharmacology, pharmacokinetics, cautions, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of conjugated estrogens, see the Estrogens General Statement 68:16.
PREPARATIONS (PR): PRIMARY TEXT: CONJUGATED ESTROGENS
[3474] Oral [3434] Tablets [3436] 0.3 mg* [1050,3403] Premarin [1080,3403] Wyeth-Ayerst [3436] 0.625 mg* [1050,3403] Premarin [1080,3403] Wyeth-Ayerst [1050,3403] Premarin Cycle Pack [1080,3403] Wyeth-Ayerst [3436] 0.9 mg [1050,3403] Premarin [1080,3403] Wyeth-Ayerst [3436] 1.25 mg* [1050,3403] Premarin [1080,3403] Wyeth-Ayerst [3436] 2.5 mg* [1050,3403] Premarin [1080,3403] Wyeth-Ayerst [3474] Parenteral [3434] For injection [3436] 25 mg [1050,3403] Premarin Intravenous [3413] (with bacteriostatic water for injection containing benzyl alcohol 2%) [1080,3403] Wyeth-Ayerst [3474] Vaginal [3434] Cream [3436] 0.0625% [1050,3403] Premarin [1080,3403] Wyeth-Ayerst
[3403] *available by nonproprietary name CONJUGATED ESTROGENS COMBINATIONS [3474] Oral [3434] Tablets [3436,3423] 0.45 mg with Meprobamate 200 mg [1070,3423] PMB 200 [1080,3423] Wyeth-Ayerst [3436,3423] 0.45 mg with Meprobamate 400 mg [1070,3423] Milprem-400 [1080,3403] Wallace [1070,3423] PMB 400 [1080,3423] Wyeth-Ayerst [3436,3423] 0.625 mg with Methyltestosterone 5 mg [1070,3423] Premarin with Methyltestosterone [1080,3423] Wyeth-Ayerst [3436,3423] 1.25 mg with Methyltestosterone 10 mg [1070,3423] Premarin with Methyltestosterone [1080,3423] Wyeth-Ayerst
REFERENCES (RF):
Note: This is a partial list of cited references. 100. National Institutes of Health. Osteoporosis. JAMA. 1984; 252:799-802. 101. Ayerst Laboratories. Premarin tablets prescribing information. New York, NY; 1986 Jul. Selected Revisions February 1990, (C) Copyright, October 1961, American Society of Hospital Pharmacists, Inc.
DESCRIPTORS: [3103] Chemistry; [3113] Chemical description; [3115] Chemical description; [3133] Physical description; [3143] Solubility; [3303] Stability; [3323] Drug compatibility; [3333] Vehicle compatibility; [3345] Storage; [3413] Other chemical ion ingredient; [3205] Pharmacology; [3003] Other drug; [3223] Therapy; [3225] Therapy; [3643] Precaution contraindication; [3653] Fetal toxicity; [3605] Adverse reaction (side effect); [3643] Precaution contraindication; [3003] Other drug; [3453] Reconstitution; [3455] Reconstitution; [3523] Dosage schedule; [3525] Dosage schedule; [3575] Administration route; [3643] Precaution contraindication; [3663] Carcinogenicity mutagenicity; [3683] Treatment toxicity; [3403] Preparations; [3413] Other chemical ion ingredient; [3423] Combination; [3434] Dosage form; [3436] Strength concentration
AHFS NO: 68.08 AHFS CLASS: ANDROGENS SUBFILE: American Hospital Formulary Service MONOGRAPH TITLE: Methyltestosterone GENERIC NAME: Methyltestosterone TRADE NAME(S): Methyltestosterone Powder (micronized) for Prescription/ Compounding Paddock/ Android-5 Brown/ Metandren Linguets Ciba/ Oreton Methyl Buccal Schering/ Testred ICN/ Virilon Star/ Android-10 Brown/ Android-25 Brown/ Metandren Ciba/ Oreton Methyl Schering/ Estratest H.S. Reid-Rowell/ Estratest Reid-Rowell/ Premarin with Methyltestosterone Wyeth-Ayerst CAS REGISTRY NO: 58-18-4
CHEMISTRY AND STABILITY (CH): PRIMARY TEXT: CHEMISTRY
[3115] Methyltestosterone is a synthetic androgenic anabolic steroid hormone.
STABILITY
[3345] Commercially available preparations of methyltestosterone should be protected from light and stored in well-closed containers at a temperature less than 40DGC, preferably between 2-30DGC, unless otherwise specified by the manufacturer.
ADDITIONAL TEXT: CHEMISTRY AND STABILITY CHEMISTRY
[3113] The drug is structurally similar to testosterone, but is methylated at the 17 position of the steroid nucleus. [3183] Methylation at the 17 position is associated with less hepatic metabolism and enhanced pharmacologic activity following oral administration compared with testosterone.
[3133,3143] Methyltestosterone occurs as white or creamy white, odorless, slightly hygroscopic crystals or a crystalline powder and is practically insoluble in water and soluble in alcohol.
STABILITY
[3303] One manufacturer states that fading of the color of the tablets will not affect potency or efficacy.
PHARMACOLOGY (PC): PRIMARY TEXT:
[3205] Endogenous androgens are essential hormones that are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics, including the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; development of male hair distribution, such as beard, pubic, chest, and axillary hair; laryngeal enlargement and thickening of the vocal cords; and alterations in body musculature and fat distribution.
ADDITIONAL TEXT: PHARMACOLOGY
[3203] Like testosterone and other androgenic anabolic hormones, methyltestosterone also produces retention of nitrogen, potassium, sodium, and phosphorus; increases protein anabolism; and decreases amino acid catabolism and urinary calcium concentrations. Nitrogen balance is improved only when there is sufficient intake of calories and protein.
[3203,3253] Androgens are responsible for the growth spurt that occurs during adolescence and for the eventual termination of linear growth that results from fusion of the epiphyseal growth centers. Although exogenous androgens accelerate linear growth rates in children, the drugs may cause a disproportionate advancement in bone maturation, and long-term administration of the drugs in prepubertal children may result in fusion of the epiphyseal growth centers and premature termination of the growth process.
[3243] Exogenous administration of androgens inhibits the release of endogenous testosterone via feedback inhibition of pituitary luteinizing hormone (LH). Following administration of large doses of exogenous androgens, spermatogenesis may also be suppressed as a result of feedback inhibition of pituitary follicle-stimulating hormone (FSH). Androgens reportedly stimulate the production of erythrkP?]Y>kPapparently by enhancing the production of erythropoietic stimulating factor.
USES (US): PRIMARY TEXT:
[3225] Methyltestosterone is used mainly for replacement or substitution of diminished or absent endogenous testicular hormone.
USES IN MALES
[3525] In males, methyltestosterone is used for the management of congenital or acquired primary hypogonadism such as that resulting from orchidectomy or from testicular failure caused by cryptorchidism, bilateral torsion, orchitis, or vanishing testis syndrome. Methyltestosterone is also used in males for the management of congenital or acquired hypogonadotropic hypogonadism such as that resulting from idiopathic gonadotropin or gonadotropin releasing hormone (luteinizing hormone releasing hormone) deficiency or from pituitary-hypothalamic injury caused by tumors, trauma, or radiation.
[3225] When the diagnosis is well established, methyltestosterone may be used to stimulate puberty in carefully selected males with delayed puberty.
OTHER USES
[3225] In females, methyltestosterone is used for the palliative treatment of androgen-responsive, advanced, inoperable, metastatic (skeletal) carcinoma of the breast in women who are 1-5 years postmenopausal. [3225] Androgen therapy has also been used in premenopausal women with carcinoma of the breast who have benefited from oophorectomy and are considered to have a hormone-responsive tumor. [3225,3640] The decision to use androgen therapy in women with carcinoma of the breast should be made by an oncologist with expertise in the treatment of this carcinoma.
[3225] Methyltestosterone has also been used for the prevention of postpartum breast pain and engorgement; however the drug does not appear to prevent or suppress lactation.
[3225,3003] In females, methyltestosterone is used in combination with estrogens for the management of moderate to severe vasomotor symptoms associated with menopause in patients who do not respond adequately to estrogens alone.
MISUSE AND ABUSE
[3213,3645] Because of their anabolic and androgenic effects on performance (ergogenic potential) and physique, androgens have been misused and abused by athletes, bodybuilders, weight lifters, and others, including high school- and college-aged individuals engaged in sports. However, such use is associated with the potential for serious adverse effects and generally is considered inappropriate and unacceptable. (See Uses: Misuse and Abuse, in Testosterone 68:08.)
ADDITIONAL TEXT: USES USES IN MALES
[3223] If any of these conditions occur before puberty, androgen replacement therapy will be necessary during adolescence for the development of secondary sexual characteristics and prolonged therapy will be required to maintain these characteristics. Prolonged androgen therapy is also required to maintain sexual characteristics in other males who develop testosterone deficiency after puberty.
[3223] These males usually have a family history of delayed puberty that is not caused by a pathologic disorder. Brief treatment with conservative doses of an androgen may occasionally be justified in these males if they do not respond to psychologic support. [3640,3223,3253] Because androgens may adversely affect bone maturation in these prepubertal males, this potential risk should be fully discussed with the patient and his parents prior to initiation of androgen therapy. (See Cautions: Pediatric Precautions.) If androgen therapy is initiated in these prepubertal males, radiographs of the hand and wrist should be obtained at 6-month intervals to determine the effect of therapy on the epiphyseal centers.
OTHER USES
[3223] Primary goals of therapy in these women include ablation of the ovaries. Other methods of counteracting estrogen activity include adrenalectomy, hypophysectomy, and/or antiestrogen therapy (e.g., tamoxifen).
[3223,3003,3643] Estrogens do not appear to be effective for the management of nervous symptoms or depression associated with menopause, and the drugs should not be used in the management of such conditions in these patients.
[3223] Although methyltestosterone has been used in other conditions (e.g., fractures, surgery, convalescence, functional uterine bleeding), there is a lack of substantial evidence that androgens are effective in these conditions. In addition, the US Food and Drug Administration (FDA) states that there currently is no evidence to support the safety and efficacy of methyltestosterone as an aphrodisiac (i.e., to arouse or increase sexual desire or to improve sexual performance).
CAUTIONS (CA): PRIMARY TEXT: ADVERSE EFFECTS
[3605] Adverse effects associated with methyltestosterone are similar to those of other synthetic or natural androgens and include acne, gynecomastia, and edema.
[3605] Oligospermia and decreased ejaculatory volume may occur in males receiving excessive dosage or prolonged administration of the drug. [3605,3250] Priapism or excessive sexual stimulation in males, especially geriatric patients, may also occur. [3645,3520] If priapism or excessive sexual stimulation develops during methyltestosterone therapy, the drug should be discontinued temporarily, since these are signs of excessive dosage; if therapy with methyltestosterone is reinstituted, a lower dosage should be used. [3605] Male pattern of baldness may also occur.
Amenorrhea and other menstrual irregularities and inhibition of gonadotropin secretion occur commonly in females. [3605,3643] Virilization, including deepening of the voice, hirsutism, and clitoral enlargement, also occur commonly in females; these changes may not be reversible following discontinuance of the drug.
[3605,3623] Hypersensitivity reactions, including skin manifestations and anaphylactoid reactions, have occurred rarely with methyltestosterone.
[3605,3240] Hypercalcemia resulting from osteolysis, especially in immobile patients and those with metastatic carcinoma of the breast, has been reported in patients receiving methyltestosterone. [3645,3603] The drug should be discontinued if hypercalcemia occurs in patients with cancer since this may indicate progression of metastases to the bone. [3605] Retention of water, sodium, chloride, potassium, and inorganic phosphates has also occurred in patients receiving the drug.
Cholestatic hepatitis and jaundice and abnormal liver function test results may occur in patients receiving 17-alpha-alkylandrogens such as methyltestosterone. [3645,3603] Methyltestosterone should be discontinued if cholestatic jaundice or hepatitis occurs, or if liver function test results become abnormal during therapy with the drug, and the etiology of these disorders should be determined. [3605] Peliosis of the liver and hepatic neoplasms, including hepatocellular carcinoma, have been reported rarely in patients receiving long-term administration of androgenic anabolic steroids. [3645,3603] Peliosis of the liver can be a life-threatening or fatal complication of androgen therapy.
[3605] Other adverse effects associated with methyltestosterone therapy include nausea, polycythemia, stomatitis in patients using buccal preparations, headache, anxiety, mental depression, generalized paresthesia, and suppression of clotting factors II, V, VII, and X. Serum cholesterol concentration may increase during androgen therapy.
PRECAUTIONS AND CONTRAINDICATIONS
[3645] Methyltestosterone shares the toxic potentials of other androgens, and the usual precautions of androgen therapy should be observed. [3645,3003] When methyltestosterone is used in combination with estrogens, the usual precautions associated with estrogen therapy should also be observed. [3645,3003,3900] (See Cautions in Conjugated Estrogens 68:16.) Clinicians prescribing estrogens should be aware of the risks associated with these drugs, and the manufacturers' labeling should be consulted for further discussion of these risks and associated precautions. Patients receiving methyltestosterone in combination with an estrogen should be given a copy of the patient labeling for the combination.
Methyltestosterone should be used with caution in patients with cardiac, renal, or hepatic dysfunction, since edema, with or without congestive heart failure, may occur as a result of sodium and water retention. [3645,3683] If edema occurs during methyltestosterone therapy and it is considered a serious complication, the drug should be discontinued; diuretic therapy may also be necessary. [3645] Liver function should be evaluated periodically during use of methyltestosterone.
Females should be carefully monitored for signs of virilization (e.g., deepening of the voice, hirsutism, clitoromegaly, menstrual irregularities) during methyltestosterone therapy.
[3645] Males should be carefully monitored for the development of priapism or excessive sexual stimulation since these are signs of excessive dosage. [3645,3253,3663] Geriatric males may be at increased risk of developing prostatic hypertrophy and carcinoma during androgen therapy.
[3645] Adult or adolescent males should be advised to report too frequent or persistent penile erections to their physician. Females should be advised to report hoarseness, acne, menstrual changes, or the growth of facial hair to their physician. All patients should be advised to report nausea, vomiting, changes in skin color, or ankle swelling to their physician.
Patients receiving high dosages of methyltestosterone should have periodic hemoglobin and hematocrit determinations, since polycythemia may occur.
[3645,3623,3053,3410] Metandren 10-mg Linguets and 25-mg tablets contain the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals.
[3645] Methyltestosterone is contraindicated in males with carcinoma of the breast or known or suspected carcinoma of the prostate. Some manufacturers state that the drug is also contraindicated in patients with cardiac, renal, or hepatic decompensation; hypercalcemia; impaired liver function; and in patients who are easily sexually stimulated.
PEDIATRIC PRECAUTIONS
[3645,3250] Androgens should be used with extreme caution in children and only by specialists who are aware of the adverse effects of these drugs on bone maturation. Methyltestosterone should be used cautiously to stimulate puberty, and only in carefully selected males with delayed puberty. (See Uses: Uses in Males.) [3605,3250] In children, methyltestosterone may accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect may result in compromised adult stature. The younger the child, the greater the risk of methyltestosterone compromising final mature stature. [3645,3250] If methyltestosterone is administered to prepubertal children (e.g., to stimulate puberty in males), the drug should be used with extreme caution, and radiographic examination of the hand and wrist should be performed every 6 months to determine the rate of bone maturation and to assess the effect of treatment on the epiphyseal centers. If methyltestosterone is to be used to stimulate puberty in a male with delayed puberty, the potential risk of therapy should be fully discussed with the patient and his parents prior to initiation of the drug. MUTAGENICITY AND CARCINOGENICITY
[3665,3643] Hepatocellular carcinoma has reportedly occurred in patients receiving long-term therapy with high dosages of androgens. [3665,3643,3250] Geriatric patients may be at increased risk of developing prostatic hypertrophy and carcinoma during androgen therapy.
PREGNANCY, FERTILITY, AND LACTATION
[3643,3655] Methyltestosterone may cause fetal harm when administered to pregnant women. [3655,3643] Since the risks clearly outweigh the possible benefits in women who are or may become pregnant, methyltestosterone is contraindicated in such women. Women who become pregnant while receiving the drug should be informed of the potential hazard to the fetus.
[3615] Increased or decreased libido has also been reported.
[3875] It is not known whether methyltestosterone is distributed into milk. [3645,3870] Because of the potential for serious adverse reactions to androgens in nursing infants, a decision should be made whether to discontinue nursing or to not use methyltestosterone, taking into account the importance of the drug to the woman.
ADDITIONAL TEXT: CAUTIONS ADVERSE EFFECTS
[3683] If edema is present before or develops during therapy, administration of diuretics may be required. [3603] Gynecomastia frequently develops and occasionally persists in patients being treated for hypogonadism.
[3603] These adverse hepatic effects may occur at relatively low doses of the drug. Drug-induced jaundice is usually reversible following discontinuance of the drug.
PRECAUTIONS AND CONTRAINDICATIONS
[3643] The drug should generally be discontinued when mild virilization is evident, since some adverse androgenic effects (e.g., voice changes) may not subside following discontinuance of the drug. The woman and physician may decide that some virilization is acceptable during treatment for carcinoma of the breast.
[3643,3250] Males, especially geriatric patients, may become overly stimulated. Stimulation to the point of increasing the nervous, mental, and physical activities beyond the patient's cardiovascular capacity should be avoided when methyltestosterone is used to treat climacteric in males. (See also Cautions: Adverse Effects.)
[3643,3623,3053,3410] Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin.
MUTAGENICITY AND CARCINOGENICITY
[3663] Regression of the tumor does not always occur following discontinuance of androgen therapy.
[3663] Following implantation of testosterone in mice, cervical-uterine tumors developed which occasionally metastasized. There is some evidence to suggest that injection of testosterone into some strains of female mice increases their susceptibility to hepatomas. Testosterone has also been shown to increase the number of tumors and decrease the degree of differentiation of chemically induced tumors in rats. It is not known whether androgens, including methyltestosterone, are mutagenic.
PREGNANCY, FERTILITY, AND LACTATION
[3653] Androgenic effects including clitoral hypertrophy, labial fusion of the external genital fold to form a scrotal-like structure, abnormal vaginal development, and persistence of a urogenital sinus have occurred in the female offspring of women who were given androgens during pregnancy. The degree of masculinization is related to the amount of drug given to the woman and the age of the fetus; masculinization is most likely to occur in a female fetus when exposure to androgens occurs during the first trimester.
[3613] Although the effect of methyltestosterone on fertility in humans has not been conclusively determined, the drug produces oligospermia and decreased ejaculatory volume in males. Priapism and excessive sexual stimulation have also occurred in males receiving the drug. (See Cautions: Adverse Effects and Precautions and Contraindications.)
DRUG INTERACTIONS (DI): PRIMARY TEXT:
[3775] Methyltestosterone may potentiate the action of oral anticoagulants, causing bleeding in some patients. [3775,3640] When methyltestosterone therapy is initiated in patients receiving oral anticoagulants, dosage reduction of the anticoagulant may be required to prevent an excessive hypoprothrombinemic response. Patients receiving oral anticoagulants should also be closely monitored when androgen therapy is discontinued. The metabolic effects of androgens may decrease blood glucose concentrations and insulin requirements in patients with diabetes.
LAB TEST INTERFERENCES (LI):
[3763] Protein bound iodine (PBI) concentrations may be decreased in some patients during methyltestosterone therapy; however, this does not appear to be clinically important. [3763,3713] Androgens may decrease thyroxine-binding globulin concentrations, resulting in decreased total serum thyroxine (T4) concentrations and increased resin uptake of triiodothyronine (T3) and T4. [3763] Free thyroid hormone concentrations remain unchanged, and there is no clinical evidence of thyroid dysfunction.
DOSAGE AND ADMINISTRATION (DO): PRIMARY TEXT: ADMINISTRATION [3575] Methyltestosterone is administered orally or intrabuccally; the drug is usually given in divided daily doses. Buccal tablets (e.g., Linguets) should be placed in the upper or lower buccal pouch between the cheek and gum, and allowed to dissolve completely; buccal tablets should not be swallowed. [3575,3640] Patients should be advised to avoid eating, drinking, chewing, or smoking while the buccal tablet is in place. Proper oral hygiene (e.g., rinsing the mouth with water) is particularly important following the use of buccal tablets. DOSAGE [3525,3830] Since intrabuccal administration of the drug bypasses metabolism in the GI tract and on first pass through the liver, dosage of buccal tablets is approximately one-half the oral dosage. DOSAGE [3526] Male Hypogonadism [3525] For replacement of endogenous testicular hormone in androgen-deficient males, the usual oral dosage of methyltestosterone is 10-50 mg daily as conventional tablets. Alternatively, buccal tablets may be administered in a dosage of 5-25 mg daily. For the management of postpubertal cryptorchidism in patients with evidence of hypogonadism, several manufacturers recommend an oral methyltestosterone dosage of 30 mg daily as conventional tablets. Alternatively, buccal tablets may be administered in a dosage of 15 mg daily. Various dosage regimens have been used to induce pubertal changes in hypogonadal males. Some clinicians recommend that lower dosages be used initially, followed by gradual increases in dosage as puberty progresses; subsequently, the dosage may be decreased to maintenance levels. Other clinicians state that higher dosages are required initially to induce pubertal changes and lower dosages can then be used for maintenance therapy after puberty. The chronologic and skeletal ages of the patient must be considered when determining the initial dosage and subsequent dosage adjustment. [3555] In general, short-term administration (e.g., 4-6 months) of methyltestosterone and dosages in the lower end of the usual range for replacement (i.e., 10 mg daily as conventional tablets or 5 mg daily as buccal tablets) are used for the treatment of delayed puberty in males. DOSAGE [3526] Inoperable Carcinoma of the Breast [3525] For the palliative treatment of advanced, inoperable, metastatic carcinoma of the breast in women, the usual oral dosage of methyltestosterone is 50-200 mg daily as conventional tablets. Alternatively, buccal tablets may be administered in a dosage of 25-100 mg daily. DOSAGE [3526] Postpartum Breast Pain and Engorgement [3525] For the prevention of postpartum breast pain and engorgement, the usual oral dosage of methyltestosterone is 80 mg daily as conventional tablets for 3-5 days after parturition. Alternatively, buccal tablets may be administered in a dosage of 40 mg daily for 3-5 days after parturition. DOSAGE [3526] Vasomotor Symptoms Associated with Menopause [3525,3003,3643] When methyltestosterone is used in combination with an estrogen (i.e., conjugated estrogens or esterified estrogens) for the short-term management of moderate to severe vasomotor symptoms associated with menopause, the lowest possible effective dosage should be used and therapy should be discontinued as soon as possible. Attempts to reduce dosage or discontinue the drugs should be made at 3- to 6-month intervals. The combinations are administered for 21 consecutive days, followed by 7 days without the drugs, and then this regimen is repeated as necessary. The manufacturers' labeling should be consulted for usual recommended dosages of the combinations. [3645,3003,3663] Women with an intact uterus receiving a combination preparation should be closely monitored for signs of endometrial carcinoma, and appropriate diagnostic measures should be employed if persistent or recurring abnormal vaginal bleeding occurs during therapy with the drugs. ADDITIONAL TEXT: DOSAGE AND ADMINISTRATION DOSAGE [3523] Dosage of methyltestosterone is variable and should be individualized according to the condition being treated, the severity of symptoms, and the patient's age, gender, and history of prior androgenic therapy.
PREPARATIONS (PR): PRIMARY TEXT: METHYLTESTOSTERONE [3434] Powder* [1050,3403] Methyltestosterone Powder (micronized) for Prescription Compounding [1080,3403] Paddock [3474] Buccal (Transmucosal) [3434] Tablets [3436] 5 mg [1050,3403] Android-5 [1080,3403] Brown [1050,3403] Metandren Linguets [1080,3403] Ciba [3436] 10 mg* [1050,3403] Metandren Linguets [3413] (with tartrazine) [1080,3403] Ciba [1050,3403] Oreton Methyl Buccal [1080,3403] Schering [3474] Oral [3434] Capsules [3436] 10 mg [1050,3403] Testred [1080,3403] ICN [1050,3403] Virilon [1080,3403] Star [3434] Tablets [3436] 10 mg* [1050,3403] Android-10 [1080,3403] Brown [1050,3403] Metandren [3403] (scored) [1080,3403] Ciba [1050,3403] Oreton Methyl [1080,3403] Schering [3436] 25 mg* [1050,3403] Android-25 [1080,3403] Brown [1050,3403] Metandren [3413] (with tartrazine [3403] scored) [1080,3403] Ciba [1050,3403] Oreton Methyl [1080,3403] Schering
[3403] *available by nonproprietary name METHYLTESTOSTERONE COMBINATIONS [3474] Oral [3434] Tablets [3436,3423] 1.25 mg with Esterified Estrogens 0.625 mg [1070,3423] Estratest H.S. [3413,3423] (with parabens and povidone) [1080,3423] Reid-Rowell [3436,3423] 2.5 mg with Esterified Estrogens 1.25 mg [1070,3423] Estratest [3413,3423] (with parabens and povidone) [1080,3423] Reid-Rowell [3436,3423] 5 mg with Conjugated Estrogens 0.625 mg [1070,3423] Premarin with Methyltestosterone [1080,3423] Wyeth-Ayerst [3436,3423] 10 mg with Conjugated Estrogens 1.25 mg [1070,3423] Premarin with Methyltestosterone [1080,3423] Wyeth-Ayerst Selected Revisions February 1990, (C) Copyright, 1959, American Society of Hospital Pharmacists, Inc.
DESCRIPTORS: [3113] Chemical description; [3115] Chemical description; [3133] Physical description; [3143] Solubility; [3183] Structure activity; [3303] Stability; [3345] Storage; [3203] Pharmacology; [3205] Pharmacology; [3243] Mechanism; [3253] Age effect; [3003] Other drug; [3213] Unlabeled investigational use; [3223] Therapy; [3225] Therapy; [3253] Age effect; [3525] Dosage schedule; [3640] Precaution contraindication; [3643] Precaution contraindication; [3645] Precaution contraindication; [3003] Other drug; [3053] Product specific information; [3240] Mechanism; [3250] Age effect; [3253] Age effect; [3410] Other chemical ion ingredient; [3520] Dosage schedule; [3603] Adverse reaction (side effect); [3605] Adverse reaction (side effect); [3613] Toxicity; [3615] Toxicity; [3623] Sensitivity photosensitivity allergy; [3643] Precaution contraindication; [3645] Precaution contraindication; [3653] Fetal toxicity; [3655] Fetal toxicity; [3663] Carcinogenicity mutagenicity; [3665] Carcinogenicity mutagenicity; [3683] Treatment toxicity; [3870] Lactation; [3875] Lactation ; [3640] Precaution contraindication; [3775] Drug interaction; [3713] Interaction mechanism; [3763] Lab test interference; [3003] Other drug; [3523] Dosage schedule; [3525] Dosage schedule; [3555] Age dosage relation; [3575] Administration route; [3640] Precaution contraindication; [3643] Precaution contraindication; [3645] Precaution contraindication; [3663] Carcinogenicity mutagenicity; [3830] Elimination; [3403] Preparations; [3413] Other chemical ion ingredient; [3423] Combination; [3434] Dosage form; [3436] Strength concentration
AHFS NO: 68.16 AHFS CLASS: ESTROGENS SUBFILE: American Hospital Formulary Service MONOGRAPH TITLE: Estrogens General Statement GENERIC NAME: Chlorotrianisene; Dienestrol; Diethylstilbestrol Diphosphate; Estradiol Cypionate; Estradiol Valerate; Estrogens, Conjugated ; Estrogens, Esterified; Estrone; Estropipate; Ethinyl Estradiol; Mestranol ; Polyestradiol Phosphate; Quinestrol CAS REGISTRY NO: 569-57-3; 84-17-3; 56-53-1; 522-40-7; 50-28-2; 313-06-4; 979-32-8; 53-16-7; 7280-37-7; 57-63-6; 72-33-3; 28014-46-2; 152-43-2
CHEMISTRY AND STABILITY (CH): PRIMARY TEXT: [3115] Estrogens are naturally occurring hormones or synthetic steroidal and nonsteroidal compounds with estrogenic activity. The estrogens can be divided into 2 groups based on their chemical structures: steroidal and nonsteroidal compounds. [3115] The natural steroidal estrogens (estradiol, estrone, estriol, equilin, and equilenin) and their conjugates are usually obtained from pregnant mares' urine or prepared synthetically. [3115] Synthetic derivatives of the natural steroidal estrogens are also available. The nonsteroidal estrogens include diethylstilbestrol (DES), dienestrol, and chlorotrianisene. ADDITIONAL TEXT: CHEMISTRY steroidal estrogen nucleus [3183] All naturally occurring estrogens are steroids which contain a cyclopentanoperhydrophenanthrene ring structure with an unsaturated A ring, a methyl group at the C 13 position, a phenolic hydroxyl group at the C 3 position, and a ketone or hydroxyl group at the C 17 position. Only a limited number of changes can be made in this basic steroid structure without losing estrogenic activity. These changes are limited to an interconversion of the hydroxyl and ketone groups or the addition of various side chains at the C 3 and C 17 positions. [3143] The natural estrogens are insoluble in water but when conjugated as the sulfates or glucuronides, these hormones become water soluble.
PHARMACOLOGY (PC): PRIMARY TEXT: [3205] Estrogens are hormones secreted principally by the ovarian follicles and also by the adrenals, corpus luteum, placenta, and testes, or are synthetic steroidal and nonsteroidal compounds. Estrogenic hormones are secreted at varying rates during the menstrual cycle throughout the period of activity of the ovaries. During pregnancy, the placenta becomes the main source of estrogens. At the menopause, ovarian secretion of estrogens declines at varying rates. The gonadotropins of the anterior pituitary regulate secretion of the ovarian hormones, estradiol and progesterone; hypothalamic control of pituitary gonadotropin production is in turn regulated by plasma concentrations of the estrogens and progesterone. This complex feedback system results in the cyclic phenomenon of ovulation and menstruation. Exogenous estrogens elicit, to varying degrees, all the pharmacologic responses usually produced by endogenous estrogens. Endogenous estrogens are essential hormones that are responsible for the normal growth and development of the female sex organs and for maintenance of secondary sex characteristics, including the growth and maturation of the vagina, uterus, and fallopian tubes; enlargement of the breasts; maintenance of tone and elasticity of urogenital structures; growth of axillary and pubic hair; and pigmentation of the nipples and genitals. Although the mechanism(s) has not been elucidated, estrogens contribute to the shaping of body contours and the skeleton, to the growth spurt that occurs during adolescence, and to the eventual termination of linear growth that results from fusion of the epiphyseal centers. Estrogens cause an increase in cell height and secretions of the cervical mucosa, thickening and cornification of the vaginal mucosa, proliferation of the endometrium, and an increase in uterine tone. [3245] Although the precise actions of estrogens on secretory activity of the pituitary have not been fully characterized, estrogens affect the release of gonadotropins (e.g., follicle-stimulating hormone (FSH)) from the pituitary, apparently as a result of feedback inhibition; the effect of estrogens on luteinizing hormone (LH) is complex and biphasic. The effects of estrogens on pituitary secretion of gonadotropins result in inhibition of lactation, inhibition of ovulation, development of a proliferative endometrium and, by inhibiting androgen secretion, a reduction of sebaceous secretions.
ADDITIONAL TEXT: PHARMACOLOGY [3203] The estrogen-stimulated endometrium may bleed within 48-72 hours after discontinuance of estrogen therapy. Paradoxically, prolonged estrogen therapy may cause shrinkage of the endometrium and an increase in size of the myometrium. Estrogens have a weak anabolic effect and may cause sodium retention with associated fluid retention and edema. Estrogens may also decrease elevated blood cholesterol and phospholipid concentrations. Estrogens affect bone by increasing calcium deposition and accelerating epiphyseal closure, following initial growth stimulation. During the preovulatory or nonovulatory phase of the menstrual cycle, estrogen is the principal determinant in the onset of menstruation. A decline of estrogenic activity at the end of the menstrual cycle also may induce menstruation; however, the cessation of progesterone secretion is the most important factor during the mature ovulatory phase of the menstrual cycle. [3243] Intracellular cytosol-binding proteins for estrogens have been identified in estrogen-responsive tissues including the female genital organs, breasts, pituitary, and hypothalamus. The exact role of cytosol-binding proteins in mediating the actions of estrogens is not fully understood, but the estrogen-binding protein complex (i.e., cytosol-binding protein and estrogen) distributes into the cell nucleus where it stimulates DNA, RNA, and protein synthesis. The presence of these receptor proteins is responsible for the palliative response to estrogen therapy in women with metastatic carcinoma of the breast.
PHARMACOKINETICS (PK): PRIMARY TEXT: ABSORPTION [3835,3573] Following oral administration, the natural, unconjugated estrogens are inactivated in the GI tract and liver; therefore, these estrogens are usually administered parenterally. [3573,3813,3835] Conjugated estrogens, some synthetic derivatives of the natural estrogens, and the nonsteroidal estrogens may be administered orally. [3813,3835] Absorption and metabolism following oral administration of these drugs is rapid and daily doses are usually required. [3815] Estrogens are readily absorbed through the skin and mucous membranes. DISTRIBUTION [3825] Estrogens are distributed throughout most body tissues. [3825,3833] Studies utilizing radioisotopes have indicated that the greatest concentrations of estrogens may occur in the fat deposits of the body; obese patients have demonstrated slower and more prolonged estrogen excretion. [3865] Estrogens are 50-80% bound to plasma proteins. Estriol is bound less to plasma proteins than is estrone or estradiol but all 3 estrogens are bound to approximately the same extent by erythrocytes. [3885] Studies using radioisotopes have demonstrated a rapid transfer of free estrone and estradiol between mother and fetus. Fetal estrogens appear to originate principally from the placenta and mother. ELIMINATION [3835] The steroidal estrogens are metabolized principally in the liver, although the kidneys, gonads, and muscle tissues may be involved to some extent. [3835] Large amounts of free estrogens are also distributed into the bile, reabsorbed from the GI tract, and recirculated through the liver where further degradation occurs. Estrogens and their metabolites are excreted mainly in urine; however, small amounts are also present in feces. The metabolic fate of the synthetic estrogens has not been fully elucidated. Diethylstilbestrol metabolism, however, appears to be similar to that of the natural estrogens with the drug being excreted mainly as the glucuronide in urine.
ADDITIONAL TEXT: PHARMACOKINETICS ABSORPTION [3823,3203] Chlorotrianisene, however, has a prolonged duration of action which may result from the storage in and slow release of estrogenically active substance from adipose tissue. Similarly, quinestrol has a prolonged duration of action as a result of its extensive storage in and slow release from adipose tissue. [3813,3573] Following IM administration of crystalline estrogen aqueous suspensions or oil solutions, absorption begins promptly and continues for several days. [3813,3843] Esterification or polymerization of the estrogens delays the absorption of these drugs following IM administration. [3823,3203] Depending on the amount of estrogen applied, systemic as well as local effects may occur following topical application. ELIMINATION [3833] The steroids and their metabolites are conjugated at the hydroxyl group of the C 3 position with sulfuric or glucuronic acid; these conjugates may undergo further metabolic change. Conjugation increases water solubility and facilitates excretion in urine. USES (US): PRIMARY TEXT: [3225] Estrogens are used in the treatment of a variety of conditions associated with a deficiency of estrogenic hormones, including moderate to severe vasomotor symptoms associated with menopause, atrophic vaginitis, kraurosis vulvae, female hypogonadism and castration, and primary ovarian failure. Estrogens may also be used in the treatment of abnormal uterine bleeding caused by hormonal imbalance not associated with organic pathology; however, progestins are usually preferred. [3225,3643] Estrogens do not appear to be effective for the management of nervous symptoms or depression associated with menopause in patients without vasomotor symptoms, and the drugs should not be used in the management of such conditions. Although estrogens have been used for the prevention of postpartum breast engorgement, data from controlled studies indicate that the incidence of substantial painful engorgement is low in untreated women, and the condition usually responds to appropriate analgesic or other supportive therapy. The benefit derived from estrogen therapy in the prevention of postpartum breast engorgement must be carefully weighed against the potential increased risk of puerperal thromboembolism associated with the use of large doses of estrogens. [3225,3900] Short-acting, oral estrogens (e.g., conjugated estrogens) may be used adjunctively with other therapeutic measures (e.g., diet, calcium, physical therapy) to retard further bone loss and the progression of osteoporosis associated with estrogen deficiency in postmenopausal women with evidence of bone loss or deficiency of bone mass. (100,101) Estrogen replacement therapy has been shown to reduce bone resorption and retard or halt bone loss in postmenopausal women; (100) however, there is no clear method for identifying those women who will develop osteoporotic fractures, and there is a lack of substantial evidence that estrogen replacement therapy decreases the incidence of osteoporotic bone fractures. (101) In case-controlled studies in white women, estrogen replacement therapy has been associated with a reduction in the incidence of hip and wrist fractures in those in whom estrogen therapy was initiated within a few years of menopause; some studies suggest that estrogens may also reduce the incidence of vertebral fracture. (100) Estrogen replacement therapy has also reportedly prevented further estrogen deficiency-induced bone loss in postmenopausal women when started up to 6 years after menopause, but did not restore bone mass to premenopausal levels; however, there is no convincing evidence that initiating estrogen therapy in elderly women will prevent osteoporosis. (100) Some clinicians suggest that cyclic, low-dose estrogen replacement therapy be considered in white women whose ovaries have been removed before the age of 50 years in whom there are no contraindications to estrogen therapy and in white women who have had a natural menopause and have no contraindications to estrogen therapy but fully understand the risks associated with estrogen use and agree to regular medical examinations. (100) However, until more data are available concerning the risks and benefits of estrogen therapy in these women, other clinicians suggest that estrogen therapy be reserved for patients with conditions associated with a high risk of osteoporosis, such as the occurrence of premature menopause. (100) Women who have had a hysterectomy have a more favorable benefit-to-risk ratio than those who have an intact uterus because of the lack of risk of endometrial carcinoma. (101) Other forms of therapy, such as calcium supplementation, should also be considered in the prevention and/or management of primary osteoporosis. (100) (See Uses: Oral Preparations, in Calcium Salts 40:12.) The efficacy of estrogen replacement therapy in non-white women has not been determined to date. (100) [3225,3643] Additional study is needed to determine the exact role and optimum regimen of estrogen and/or other modalities in the prevention of primary osteoporosis. (100) Estrogens are used in the palliative treatment of advanced, inoperable, metastatic carcinoma of the breast in postmenopausal women and in men; however, because tamoxifen appears to be at least as effective as estrogen therapy in postmenopausal women and causes a lower incidence of severe adverse effects, tamoxifen is preferred by some clinicians. Estrogens are not used in the treatment of breast cancer in premenopausal women because the drugs may potentially stimulate tumor growth rather than inhibit it. In males, estrogens are used for the palliative treatment of advanced, inoperable carcinoma of the prostate; however, the risk of adverse cardiovascular effects of the drugs must be considered. [3225,3643,3900] Estrogens have not been shown to be effective for any purpose during pregnancy, and use of the drugs in pregnant women may cause severe harm to the fetus. (See Cautions: Pregnancy and Lactation.) [3225,3003,3900,3643,3653] Estrogens are also used in combination with progestins for ovulation control in the prevention of conception. (See Uses in Estrogen-Progestin Combinations 68:12.) [3225,3900] For information on the uses of specific estrogens, see the individual monographs in 68:16.
ADDITIONAL TEXT: USES [3223] The specific role of estrogen therapy compared with other therapies (e.g., chemotherapy, orchiectomy) in the treatment of prostatic cancer has not been clearly determined, and patients should generally be referred to physicians who are actively engaged in the investigation of the disease and are therefore familiar with the latest and most advantageous forms of therapy. Estrogen therapy is currently considered a therapy of choice for patients with inoperable prostatic tumors, for patients who refuse orchiectomy, and for patients whose disease progresses despite orchiectomy in whom the benefits of estrogen use are considered to outweigh the risk of adverse effects.
CAUTIONS (CA): PRIMARY TEXT: [3605] Numerous adverse effects have been reported in patients receiving estrogens and these may be similar to the adverse effects associated with estrogen-progestin oral contraceptives. [3605,3643,3503] Although most of the serious adverse effects of estrogen-progestin oral contraceptives (e.g., thromboembolic disorders, hepatocellular adenoma) generally have not been associated with postmenopausal estrogen therapy, this may reflect the comparatively low dosages of estrogens used in postmenopausal women. When larger dosages of estrogen are used (e.g., for the palliative treatment of carcinoma of the breast or prostate, for the prevention of postpartum breast engorgement), an increased risk of the serious adverse effects may occur. [3605,3643,3900] For additional information on the adverse effects, precautions, and contraindications associated with estrogens, see Cautions in Estrogen-Progestin Combinations 68:12. GI EFFECTS [3605] Nausea has been frequently associated with estrogen therapy. Other adverse GI effects include vomiting, abdominal cramps, bloating, and diarrhea. Changes in appetite and changes in weight may also occur. DERMATOLOGIC EFFECTS [3605] The most frequent adverse dermatologic reaction associated with estrogen therapy is chloasma or melasma. [3605] Other dermatologic reactions include erythema multiforme, erythema nodosum, and hemorrhagic eruption. Hirsutism and alopecia have also occurred. Porphyria cutanea has reportedly been adversely affected in some women receiving estrogen therapy. CARDIOVASCULAR EFFECTS [3606] Elevated Blood Pressure [3605] Increases in blood pressure may occur in women receiving estrogens. Blood pressure elevations are usually minor, but clinically important hypertension may occur in some women. [3645] Women receiving high dosages of estrogens or those with a history of hypertension, preexisting renal disease, a history of toxemia or elevated blood pressure during pregnancy, a familial tendency toward hypertension or its consequences, or a history of excessive weight gain or fluid retention during the menstrual cycle may be at increased risk of developing elevated blood pressure during estrogen therapy and, therefore, should be monitored closely. Even though elevated blood pressure may remain within the normal range, the clinical implications of elevations should be considered in all patients. All women, but particularly those with other risk factors for cardiovascular disease or stroke and those receiving high dosages of estrogens, should have blood pressure measurements before an estrogen is prescribed and at regular intervals during therapy. Estrogens should be discontinued if the patient becomes hypertensive during therapy. CARDIOVASCULAR EFFECTS [3606] Thromboembolic Disorders [3605,3643] Although an increased rate of thromboembolic and thrombotic disorders has not been found in postmenopausal women receiving estrogens, the possibility that such an increase may occur or that subgroups of women who have underlying risk factors or who are receiving relatively large dosages of estrogens may have an increased risk should be considered. [3605] In addition, in a study in men, large dosages (i.e., 5 mg daily) of conjugated estrogens have been shown to increase the risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. [3645] The clinician and the patient using estrogens should be alert to the earliest signs and symptoms of thromboembolic and thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis). Estrogen therapy should be discontinued immediately when any of these disorders occurs or is suspected. (See Cautions: Precautions and Contraindications.) CARDIOVASCULAR EFFECTS [3606] Other Cardiovascular Effects [3605] Estrogens may cause some degree of fluid retention and edema. ENDOCRINE AND METABOLIC EFFECTS [3605] Endocrine function test results (e.g., glucose tolerance, thyroid function) may be altered in patients receiving large dosages of estrogens. (See Laboratory Test Interferences.) Decreased glucose tolerance has occurred in women receiving estrogen-containing oral contraceptives and may occur in patients receiving large dosages of estrogens. [3645] Prediabetic and diabetic patients should be carefully monitored during estrogen therapy. [3605] Increased serum triglyceride concentrations have occurred in some women receiving estrogen-containing oral contraceptives and may occur during therapy with estrogens, especially when large dosages are used. [3645,3603] The clinical importance of these alterations in lipid and lipoprotein concentrations has not been established; however, it may be advisable to avoid use of estrogens in women with elevated serum lipid concentrations. [3605] Estrogens have reportedly caused severe hypercalcemia in patients with metastatic carcinoma of the breast. [3645] If severe hypercalcemia occurs, estrogen therapy should be discontinued and appropriate therapy to decrease serum calcium concentration should be instituted. [3605,3643] Estrogen-containing oral contraceptives have reportedly caused folate deficiency possibly by interfering with polyglutamate (dietary folate) absorption, and supplementary folic acid therapy may be required; the possibility that folate deficiency may occur in patients receiving estrogens should be considered. HEPATIC EFFECTS [3605,3643] Liver function test results may be altered in patients receiving estrogen therapy; if results of these tests are abnormal, they should be repeated 2 months after discontinuance of the drug. [3605,3643] Cholestatic jaundice has been reported in women receiving estrogen-containing oral contraceptives, and the possibility that this effect may occur during estrogen therapy should be considered. [3645] If jaundice occurs during estrogen therapy, the drug should be discontinued. [3605,3643] Estrogens may precipitate hepatic forms of porphyria, and the drugs probably should not be used by women who have a familial history history of hepatic porphyrias, since the occurrence of these conditions appears to be genetically determined. [3645] Steroid hormones (including estrogens) may be poorly metabolized in patients with hepatic dysfunction; therefore, estrogens should be administered with caution to these individuals. [3605] Liver tumors have been associated with use of estrogen-containing oral contraceptives. [3645] Although benign hepatocellular adenomas have not been reported to date with estrogens, the possibility of a liver tumor should be considered in any patient receiving an estrogen who develops sudden severe abdominal pain or shock. GENITOURINARY EFFECTS [3605] Breakthrough bleeding, spotting, changes in menstrual flow, missed menses (during use), or amenorrhea (after use) may occur in women receiving estrogen therapy. Dysmenorrhea and a premenstrual-like syndrome may also occur. [3645] In patients with breakthrough bleeding or irregular vaginal bleeding, nonfunctional causes should be considered. Appropriate diagnostic procedures should be performed in patients with undiagnosed persistent or recurrent vaginal bleeding. [3605] Changes in cervical erosion and secretions may occur during estrogen therapy. In addition, preexisting uterine leiomyoma may increase in size in women receiving estrogens. A cystitis-like syndrome has been reported but has not been definitely attributed to estrogens. An increased incidence of Candida vaginitis has been associated with estrogen therapy. NERVOUS SYSTEM EFFECTS [3605] Mental depression may occur in patients receiving estrogens. [3645] Patients with a history of mental depression should be observed carefully and estrogens discontinued if severe depression recurs during use. [3605] Dizziness, changes in libido, and chorea have been reported in patients receiving estrogens. Headache, especially migraine headache, may occur during estrogen therapy. [3645] Estrogens should be discontinued and the cause evaluated when migraine occurs or is exacerbated, or when a new headache pattern develops that is recurrent, persistent, and/or severe. OCULAR EFFECTS [3605] Estrogens have been reported to produce keratoconus (steepening or corneal curvature) and intolerance to contact lenses. [3645] Contact lens wearers who develop visual disturbances or changes in lens tolerance during estrogen therapy should be assessed by an ophthalmologist; temporary or permanent cessation of contact lens wear should be considered. [3645] If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; or retinal vascular lesions occur during therapy with an estrogen, the drug should be discontinued and appropriate diagnostic and therapeutic measures instituted. HEMATOLOGIC EFFECTS [3605] Changes in various blood factors and blood components have been observed in women receiving estrogen-containing oral contraceptives and may occur in patients receiving estrogens; however, further studies are required before the clinical importance of these changes can be established. OTHER ADVERSE EFFECTS [3605] Breast changes, including tenderness, enlargement, and secretion, may occur during estrogen therapy. Estrogen use and oral contraceptive use appear to be associated with an increased risk of gallbladder disease. PRECAUTIONS AND CONTRAINDICATIONS [3645] Use of estrogens, especially in large dosages, may be associated with an increased risk of several serious conditions including thromboembolism, stroke, myocardial infarction, liver tumor, gallbladder disease, visual disturbances, fetal abnormalities, malignancy, and hypertension. Clinicians prescribing estrogens should be aware of the risks associated with the use of estrogens; the manufacturers' labeling also should be consulted for further discussion of these risks and associated precautions. [3645,3003] When estrogens are used in combination with other drugs (e.g., androgens, meprobamate, progestins), the usual precautions associated with the other drugs should also be observed. If a progestin is administered concomitantly with estrogen therapy, potential risks may include adverse effects on carbohydrate and lipid metabolism. (101) [3645] Patients receiving estrogens should be under the supervision of a physician who should inform them of the possible risks involved. Patients receiving estrogens should also be given a copy of the patient labeling for the drugs. A complete medical and family history should be taken prior to initiation of estrogen therapy and periodically thereafter. Estrogens should generally not be prescribed for longer than 1 year without a repeat physical examination being performed. Physical examination should include special attention to blood pressure, breasts, abdomen, and pelvic organs and should include a Papanicolaou test (Pap smear) and relevant laboratory tests. Patients receiving estrogens should be informed to notify their physician if signs or symptoms of thromboembolic or thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis) occur, including sudden severe headache or vomiting, disturbance of vision or speech, sudden partial or complete loss of vision, dizziness or faintness, weakness or numbness in an extremity, sharp or crushing chest pain, unexplained cough, hemoptysis, sudden shortness of breath, calf pain, or heaviness in the chest. Patients receiving large dosages of an estrogen (e.g., 5 mg of conjugated estrogens daily) may be at increased risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis, since males being treated with such dosages for prostatic and breast cancer have been shown to have an increased risk for developing these conditions. Patients receiving estrogens should also be advised to inform their physician if severe abdominal pain or an abdominal mass (indicating a possible liver tumor), jaundice, severe mental depression, or unusual bleeding occurs. Women receiving estrogens should be instructed in self-examination of their breasts and should report lumps in the breast to their physician. Estrogens should be used with caution, and only with careful monitoring, in patients with conditions that might be aggravated by fluid retention (e.g., asthma; seizure disorders; migraine; or cardiac, renal, or hepatic insufficiency); in patients with cerebrovascular or coronary artery disease (including myocardial infarction); and in women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammographic findings (see Cautions: Carcinogenicity). Because an increased risk of postsurgery thromboembolic complications may occur during estrogen therapy, estrogens should be discontinued, whenever feasible, at least 4 weeks prior to surgery that is associated with an increased risk of thromboembolism or prolonged immobilization. The decision as to when to resume estrogen therapy following major surgery or immobilization should be based on the risks of postsurgery thromboembolic complications and the need for such therapy. Because estrogens influence the metabolism of calcium and phosphorus, the drugs should be used with caution in patients with renal insufficiency and in patients with metabolic bone diseases that are associated with hypercalcemia. [3645,3653] Estrogens are contraindicated in patients with known or suspected pregnancy, undiagnosed abnormal genital bleeding, thrombophlebitis or thromboembolic disorders, or known or suspected estrogen-dependent neoplasia. [3645] Estrogens are also contraindicated in patients with a history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used for the palliative treatment of carcinoma of the breast), and in patients with known or suspected carcinoma of the breast (except when used for the palliative treatment of metastatic disease in appropriately selected individuals). PEDIATRIC PRECAUTIONS [3645,3253] Safety and efficacy of estrogens in children have not been established. Estrogen therapy should be used with caution in young individuals in whom bone growth is not yet complete, since estrogens may cause premature closure of the epiphyses. CARCINOGENICITY [3665] Prolonged continuous administration of natural or synthetic estrogen in certain animal species increases the frequency of certain benign or malignant tumors including those of the breast, cervix, uterus, vagina, ovary, pituitary, and liver. Several retrospective case-control studies have shown an increased relative risk of endometrial carcinoma in postmenopausal women who received prolonged estrogen replacement therapy for relief of menopausal symptoms. [3663,3645] To minimize the risk of endometrial carcinoma in women receiving estrogens for the management of menopausal symptoms, the drugs should be administered at the lowest possible effective dosage and therapy should be discontinued as soon as possible. [3663,3645] Close clinical surveillance of all women receiving estrogens is essential. Appropriate diagnostic measures should be undertaken to rule out malignancy in all women with undiagnosed persistent or recurrent abnormal vaginal bleeding. [3663,3645] Women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammographic findings should be closely monitored if they elect to use estrogens. PREGNANCY AND LACTATION [3655] Estrogens can cause serious fetal toxicity when administered to pregnant women. An increased risk of congenital anomalies, including cardiovascular and limb defects, has been reported following use of sex hormones. [3655,3643] If estrogens are inadvertently administered during pregnancy or if the patient becomes pregnant while receiving an estrogen, the woman should be informed of the potential hazard to the fetus, and the advisability of continuing the pregnancy should be weighed against the risks of exposure of the fetus to the drug. [3645,3873] Because of the potential for serious adverse reactions to estrogens in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. (101)
ADDITIONAL TEXT: CAUTIONS DERMATOLOGIC EFFECTS [3603] Women who have had melasma during pregnancy appear to be most susceptible. Irregular brown macules may develop slowly on the face within 1 month to 2 years following initiation of estrogen therapy. The macules fade more slowly than in melasma gravidarum and may be permanent. CARDIOVASCULAR EFFECTS [3606] Elevated Blood Pressure [3603] Elevated blood pressure may gradually decrease or persist after discontinuance of estrogen therapy. [3603,3243] The precise cause of increased blood pressure is not known, but it may result from a stimulatory effect of estrogen on the renin-angiotensin system. CARDIOVASCULAR EFFECTS [3606] Thromboembolic Disorders [3603,3003] Oral contraceptive use is associated with an increased risk of thromboembolic and thrombotic disorders including thrombophlebitis, pulmonary embolism, stroke, subarachnoid hemorrhage, and myocardial infarction. Retinal thrombosis and mesenteric thrombosis have also been reported in women receiving oral contraceptives. [3603,3003,3500] A positive association between thromboembolic disorders and estrogen dosage exists. [3603,3003] An increased risk of postsurgery thromboembolic complications has also been reported in patients receiving oral contraceptives. CARDIOVASCULAR EFFECTS [3606] Other Cardiovascular Effects [3643] Estrogen therapy should therefore be used with caution in patients with conditions that might be aggravated by fluid retention. (See Cautions: Precautions and Contraindications.) ENDOCRINE AND METABOLIC EFFECTS [3773,3643] A possible additive effect with other drugs that decrease serum folate concentrations should also be considered. HEPATIC EFFECTS [3603] Increased sulfobromophthalein retention has reportedly occurred in women receiving estrogen-containing oral contraceptives, as a result of interference with the transfer of dye conjugates from liver cells into bile; uptake, conjugation, and storage do not appear to be affected. Less frequently, increased serum aminotransferase and alkaline phosphatase concentrations have occurred. Liver function test results usually return to normal within several weeks after estrogen-containing oral contraceptives are discontinued; occasionally, however, abnormal test results may persist for longer periods. [3643] The possibility that these alterations in liver function test results may occur in patients receiving estrogens should be considered. [3603] Cholestasis is manifested by the development of malaise, anorexia, and pruritus about 2 weeks to 2 months after the start of therapy. Occasionally, arthralgia, fever, and rash may occur. Serum bilirubin may range from 3-10 mg/dL and is mostly conjugated. Women with a history of jaundice during pregnancy have an increased risk of jaundice recurrence while receiving estrogen-containing oral contraceptives. [3603] Liver tumors have been benign or malignant and have occurred during short-term and long-term use of oral contraceptives. [3603,3643] Most commonly, liver tumors are benign hepatocellular adenomas and occur only rarely in oral contraceptive users; however, they may result in death because their vascularity predisposes them to rupture and cause massive hemorrhage. NERVOUS SYSTEM EFFECTS [3603] In a few women receiving estrogen-containing oral contraceptives, mental depression was severe and led to suicidal behavior. OCULAR EFFECTS [3603] Although neuro-ocular lesions such as optic neuritis or retinal thrombosis have been associated with use of estrogen-containing oral contraceptives, these lesions have not been reported to date with estrogens. HEMATOLOGIC EFFECTS [3603] Increases in prothrombin and blood coagulation factors VII, VIII, IX, and X levels and decreases in antithrombin III activity may occur in patients receiving estrogens. Estrogens may also enhance norepinephrine-induced platelet aggregation. OTHER ADVERSE EFFECTS [3603] In one study, an increased risk of gallbladder disease occurred after 2 years of use of the drugs and doubled after 4 or 5 years of use. In another study, an increased risk of gallbladder disease was apparent between 6-12 months of use. CARCINOGENICITY [3663] This risk was independent of other known risk factors for endometrial carcinoma and appeared to depend on duration and dosage of estrogen therapy. [3663,3643] Because of the increased risk of endometrial carcinoma associated with prolonged estrogen therapy, patients receiving prolonged treatment with the drugs should be evaluated at least twice yearly to reassess the need for continued therapy. [3663,3643,3523] Since it appears that the risk of endometrial carcinoma associated with cyclic administration of low dosages of estrogen is less than that associated with continuous administration, it is generally recommended that a cyclic regimen be used. [3663,3643,3003,3523] In addition, use of progestin therapy for 7 or more days of a cycle of estrogen administration has been associated with a decreased incidence of endometrial hyperplasia; however, it has not been clearly established whether addition of progestin therapy will reduce the risk of developing endometrial carcinoma. (101) (See Dosage and Administration: Dosage.) [3663] Currently, there is no evidence that estrogens derived from natural sources are more or less hazardous than synthetic estrogens at equiestrogenic dosages. [3663] Most studies have shown no increased risk of breast cancer in postmenopausal women receiving estrogens; however, some data have suggested an association between estrogen use and the risk of breast cancer. PREGNANCY AND LACTATION [3003,3653,3900] In utero exposure of females to diethylstilbestrol (DES), a nonsteroidal estrogen, is associated with an increased risk of developing a rare form of vaginal or cervical cancer in later life. (See Cautions: Pregnancy, Fertility, and Lactation, in Diethylstilbestrol 68:16.) [3003,3653] In addition, such exposure to DES causes epithelial changes in the vagina and cervix in 30-90% of these exposed female offspring. Although similar data are not available for other estrogens, it cannot be presumed that they would not induce similar changes. [3653,3223,3643] Although estrogens were previously used to treat threatened or habitual abortion, there is considerable evidence that estrogens are ineffective for these uses; in addition, the potential for adverse effects of the drugs on the fetus exists.
ACUTE/CHRONIC TOXICITY (TO):
[3613] Acute overdosage of large doses of oral contraceptives in chidren reportedly produces almost no toxicity except nausea and vomiting. Acute overdosage of estrogens may cause nausea, and withdrawal bleeding may occur in females.
DRUG INTERACTIONS (DI): PRIMARY TEXT: HEPATIC MICROSOMAL ENZYME INDUCTION [3715] Rifampin reportedly decreases estrogenic activity during concomitant use with estrogens. This effect has been attributed to enhanced metabolism of estrogen, presumably by induction of hepatic microsomal enzymes. CORTICOSTEROIDS [3775,3643] Patients receiving concomitant estrogen and corticosteroid therapy should be observed for signs of excessive corticosteroid effects, and alterations in corticosteroid dosage may be necessary when estrogens are started or discontinued.
ADDITIONAL TEXT: DRUG INTERACTIONS HEPATIC MICROSOMAL ENZYME INDUCTION [3773] It has been suggested that a similar effect may occur during concomitant therapy with other known inducers of hepatic microsomal enzymes including barbiturates, carbamazepine, phenylbutazone, phenytoin, and primidone. CORTICOSTEROIDS [3773] Estrogens have been reported to enhance the anti-inflammatory effect of hydrocortisone in patients with chronic inflammatory skin diseases. [3713] It has been suggested that estrogens may decrease the hepatic metabolism of corticosteroids and/or alter serum corticosteroid protein binding. ORAL ANTICOAGULANTS [3773] Estrogens may decrease the action of oral anticoagulants. [3773,3643] When estrogen therapy is initiated in patients receiving anticoagulants, an increase in anticoagulant dosage may be required.
LAB TEST INTERFERENCES (LI):
[3763,3900] Estrogen-containing oral contraceptives have caused abnormal thyroid function test results. (See Effects on Thyroid in Cautions: Endocrine and Metabolic Effects, in Estrogen-Progestin Combinations 68:12.) Estrogen-containing oral contraceptives have altered response to the metyrapone test (see Laboratory Test Interferences in Estrogen-Progestin Combinations 68:12) and liver function test results (see Cautions: Hepatic Effects, in Estrogen-Progestin Combinations 68:12). [3763] Estrogen-containing oral contraceptives have also caused decreased pregnanediol excretion. [3763,3643] The manufacturers state that the pathologist should be advised of estrogen use when relevant specimens from a patient exposed to estrogens are submitted.
DOSAGE AND ADMINISTRATION (DO): PRIMARY TEXT: ADMINISTRATION [3575] Estrogens may be administered orally, parenterally, intravaginally, or topically. Oral preparations and parenteral preparations with a short duration of action are usually more suitable for treatment of estrogen-deficiency states requiring cyclic therapy, while longer-acting preparations may be more useful for long-term treatment of prostatic and breast carcinoma in which high estrogen dosage is required. DOSAGE [3525] Dosage equivalencies for estrogens have not been clearly established, and reported comparative values vary greatly. The dosage range of estrogens is generally wide, and dosage should be individualized according to the condition being treated and the response and tolerance of the patient. To minimize the risk of adverse effects, the lowest possible effective dosage should be used. When short-term estrogen therapy is indicated (e.g., for the management of vasomotor symptoms associated with menopause; atrophic vaginitis; kraurosis vulvae), therapy should be discontinued as soon as possible; attempts to reduce dosage or discontinue the drug should be made at 3- to 6-month intervals. Estrogen therapy is usually administered cyclically. The drugs are usually given once daily for 3 weeks, followed by 1 week without the drugs, and then this regimen is repeated as necessary. ADDITIONAL TEXT: DOSAGE AND ADMINISTRATION DOSAGE [3523,3003,3683] Addition of progestin therapy for 7 or more days of a cycle of estrogen administration has been associated with a decreased incidence of endometrial hyperplasia. Morphologic and biochemical studies of the endometrium suggest that 10-13 days of progestin are needed to provide maximum maturation of the endometrium and to eliminate any hyperplastic changes. [3523,3003,3643,3663] It has not been clearly established whether addition of progestin therapy will reduce the risk of developing endometrial carcinoma. [3003,3643,3523] When a progestin is used in conjunction with cyclic estrogen administration, the usual precautions associated with progestin therapy should be observed. Clinicians prescribing progestins should be aware of the risks associated with these drugs and the manufacturers' labeling should be consulted. The choice and dosage of a progestin may be important factors in minimizing potential adverse effects. [3900] For further information on chemistry and stability, pharmacology, pharmacokinetics, uses, cautions, and dosage and administration of estrogens, see the individual monographs in 68:16. See also Estrogen-Progestin Combinations 68:12.
REFERENCES (RF):
Note: This is a partial list of cited references. 100. National Institutes of Health. Osteoporosis. JAMA. 1984; 252:799-802. 101. Ayerst Laboratories. Premarin tablets prescribing information. New York, NY; 1986 Jul. Selected Revisions February 1988, (C) Copyright, May 1969, American Society of Hospital Pharmacists, Inc.
DESCRIPTORS: [3115] Chemical description; [3143] Solubility; [3183] Structure activity; [3203] Pharmacology; [3205] Pharmacology; [3243] Mechanism; [3245] Mechanism; [3203] Pharmacology; [3573] Administration route; [3813] Absorption; [3815] Absorption; [3823] Distribution; [3825] Distribution; [3833] Elimination; [3835] Elimination; [3843] Biopharmaceutics; [3865] Kinetic parameter; [3885] Placental transfer; [3003] Other drug; [3223] Therapy; [3225] Therapy; [3643] Precaution contraindication; [3653] Fetal toxicity; [3003] Other drug; [3223] Therapy; [3243] Mechanism; [3253] Age effect; [3500] Dose; [3503] Dose; [3523] Dosage schedule; [3603] Adverse reaction (side effect); [3605] Adverse reaction (side effect); [3643] Precaution contraindication; [3645] Precaution contraindication; [3653] Fetal toxicity; [3655] Fetal toxicity; [3663] Carcinogenicity mutagenicity; [3665] Carcinogenicity mutagenicity; [3773] Drug interaction; [3873] Lactation; [3613] Toxicity; [3643] Precaution contraindication; [3713] Interaction mechanism; [3715] Interaction mechanism; [3773] Drug interaction; [3775] Drug interaction; [3643] Precaution contraindication; [3763] Lab test interference; [3003] Other drug; [3523] Dosage schedule; [3525] Dosage schedule; [3575] Administration route; [3643] Precaution contraindication; [3663] Carcinogenicity mutagenicity; [3683] Treatment toxicity ?B DRUG3