اتینیل استرادیول
Ethinyl Estradiol and Ethynodiol Diacetate (Demulen)
اتینیل استرادیول

نام ژنریک

Ethinyl Estradiol

شکل دارویی

اشكال دارويي:


Tablet: 0.05, 0.5 mg

موارد مصرف

موارد و مقدار مصرف


الف) سرطان پستان (حداقل پنج سال بعد از يائسگي).


بزرگسالان: مقدار يک ميلي گرم سه بار در روز از راه خوراکي مصرف مي‌شود.


ب) کم کاري تخمدان.


بزرگسالان: مقدار 0.05 ميلي گرم 3-1 بار در روز به مدت دو هفته از ماه مصرف مي‌شود. پس از آن، به مدت دو هفته درمان با پروژسترون پيگيري مي‌شود. اين دوره درمان به مدت 6-3 ماه ادامه مي‌يابد و سپس، دو ماه مصرف دارو قطع مي‌شود.


پ) نشانه‌هاي يائسگي.


بزرگسالان: مقدار mg/day 0.05 - 0.02 به مدت سه هفته مصرف مي‌شود و سپس يک هفته مصرف دارو قطع مي‌شود.


ت) پرخوني پستان بعد از زايمان.


بزرگسالان: مقدار mg/day 1-0.5 به مدت سه روز مصرف مي‌شود و سپس طي هفت روز مقدار مصرف به mg/day 0.1 کاهش مي‌يابد، و بعد از آن مصرف دارو قطع مي‌شود.


ث) سرطان پروستات.


بزرگسالان: مقدار mg/day 2-0.15 از راه خوراکي مصرف مي‌شود.

موارد منع مصرف

تداخل دارويي


مصرف همزمان با داروهايي که موجب القاي متابوليسم کبدي مي‌شوند (مانند ريفامپين، باربيتوراتها، پريميدون، کاربامازپين و فني توئين) ممکن است موجب کاهش اثرات استروژني داروي مصرف شده شود. اين داروها سرعت متابوليسم بعضي از داروهاي ديگر را نيز افزايش مي‌دهند.


اتينيل استراديول ممکن است غلظت خوني گلوکز را در بيماران ديابتي افزايش دهد. بنابراين، در صورت مصرف همزمان، تنظيم مقدار مصرف انسولين يا داروهاي خوراکي پايين آورنده قند خون ضروري خواهد شد.


مصرف همزمان با داروهاي ضد انعقاد ممکن است اثرات داروهاي ضد انعقاد شبه وارفارين را کاهش دهد.


مصرف همزمان با آدرنوکورتيکواستروئيدها يا هورمون آدرنوکورتيکوتروپين خطر تجمع مايعات و الکتروليتها را افزايش مي‌دهد.

موارد قابل توجه

-

تداخل دارویی

اثر بر آزمايشهاي تشخيصي


درمان با اتينيل استراديول موجب افزايش احتباس سولفوبروموفتالئين، پروترومبين و فاکتورهاي انعقادي VII تا X، و قابليت تجمع پلاکت ناشي از نوراپي نفرين مي‌شود. غلظت گلوبولين پيوند يافته به هورمونهاي تيروئيد ممکن است افزايش يابد که به افزايش غلظت هورمونهاي تام تيروئيد (اندازه گيري شده توسط يد پيونديافته به پروتئين يا تيروکسين) و کاهش برداشت رزيني تري يدو تيرونين آزاد
منجر مي‌شود. غلظت سرمي فولات، پيريدوکسين و آنتي ترومبين ممکن است کاهش يابد.

مکانیزم اثر

اثر بر آزمايشهاي تشخيصي


درمان با اتينيل استراديول موجب افزايش احتباس سولفوبروموفتالئين، پروترومبين و فاکتورهاي انعقادي VII تا X، و قابليت تجمع پلاکت ناشي از نوراپي نفرين مي‌شود. غلظت گلوبولين پيوند يافته به هورمونهاي تيروئيد ممکن است افزايش يابد که به افزايش غلظت هورمونهاي تام تيروئيد (اندازه گيري شده توسط يد پيونديافته به پروتئين يا تيروکسين) و کاهش برداشت رزيني تري يدو تيرونين آزاد
منجر مي‌شود. غلظت سرمي فولات، پيريدوکسين و آنتي ترومبين ممکن است کاهش يابد.

فارماكوكینتیك

موارد منع مصرف و احتياط


موارد منع مصرف: ترومبوفلبيت يا ترومبوآمبولي (به دليل همراهي اين دارو با اختلالات ترومبوآمبوليک)، کارسينوم حساس به استروژن (سرطان پستان يا مجاري تناسلي) (ممکن است موجب رشد تومور شود)، خونريزي غيرطبيعي و تشخيص داده نشده دستگاه تناسلي، بارداري (ممکن است موجب مسموميت جنين شود)، شيردهي (به دليل عوارض جانبي بالقوه بر روي شيرخوار).


موارد احتياط :


الف) اختلالاتي که با تجمع مايعات و الکتروليتها تشديد مي‌شوند، مانند آسم، اختلالات تشنجي، ميگرن، اختلال عملکرد قلب، کليه يا کبد.


ب) وضعيت زناني که ندولهاي پستان، بيماري فيبروسيستيک پستان و يا سابقه خانوادگي سرطان پستان دارند، بايد به دقت پيگيري شود.


پ) به دليل خطر بروز ترومبوآمبولي، درمان با اين دارو بايد حداقل يک هفته قبل از انجام اعمال جراحي انتخابي، که با افزايش خطر ترومبوآمبولي همراه هستند، قطع شود.

سایر اطلاعات

طبقه‌‌بندي فارماكولوژيك: استروژن.


طبقه‌‌بندي درماني: جانشين استروژن، ضد نئوپلاسم (استروژن).


طبقه‌بندي مصرف در بارداري: رده X


عوارض جانبي


اعصاب مرکزي: سردرد، سرگيجه، کره، افسردگي، تغيير در ميل جنسي، لتارژي.


قلبي ـ ‌عروقي: ترومبوفلبيت، ترومبوآمبولي، زيادي فشار خون، ادم.


پوست: ملاسما، کهير، آکنه، سبوره، پوست چرب، پرمويي يا ريزش مو.


چشم: تشديد نزديک بيني يا آستيگماتيسم، عدم تحمل عدسيهاي تماسي.


دستگاه گوارش: تهوع، استفراغ، کرامپهاي شکمي، نفخ، اسهال، يبوست، بي اشتهايي، افزايش اشتها، تغيير وزن بدن.


ادراري ـ تناسلي:


در زنان: خونريزي نابهنگام، تغيير در مقدار خونروي، قاعدگي دردناک، آمنوره، ساييدگي گردن رحم، تغيير در ترشحات گردن رحم، بزرگ شدن فيبرومهاي رحم، کانديدياز مهبلي؛


و در مردان: ژنيکوماستي، آتروفي بيضه، ناتواني جنسي.


کبد: يرقان انسدادي.


متابوليک: زيادي قند و کلسيم خون، کمبود اسيد فوليک.


ساير عوارض: تغييرات پستان (حساس شدن به لمس يا فشار، بزرگي، ترشحات)، کرامپهاي ساق پا.


مسموميت و درمان


تظاهرات باليني: مسموميت شديد بعد از مصرف بيش از حد دارو گزارش نشده است. مي‌توان بروز تهوع را انتظار داشت.


درمان: شامل اقدامات حمايتي است.


مصرف در سالمندان: مصرف اين دارو در بيماراني که وضعيت آنها با احتباس مايعات تشديد مي‌شود، بايد با احتياط همراه باشد.


مصرف در شيردهي: مصرف اتينيل استراديول در شيردهي منع شده است.

Ethinyl Estradiol and Ethynodiol Diacetate (Demulen)

Demulen
(ethinyl estradiol; ethynodial diacetate)

DRUG DESCRIPTION

The chemical name for ethyndiol diacetate is 19-nor-17alpha-pregn-4-en-20-yne-3beta,17-diol diacetate, and for ethinyl estradiol it is 19-nor- 17alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol.

Demulen (ethinyl estradiol and ethynodiol diacetate) 1/35-21 and Demulen (ethinyl estradiol and ethynodiol diacetate) 1/35-28: Each white tablet contains 1 mg of ethynodiol diacetate and 35 mcg of ethinyl estradiol, and the inactive ingredients include calcium acetate, calcium phosphate, corn starch, hydrogenated castor oil, and povidone. Each blue tablet in the Demulen (ethinyl estradiol and ethynodiol diacetate) 1/35-28 package is a placebo containing no active ingredients, and the inactive ingredients include calcium sulfate, corn starch, FD&C Blue No. 1 Lake, magnesium stearate, and sucrose.

Demulen (ethinyl estradiol and ethynodiol diacetate) 1/50-21 and Demulen (ethinyl estradiol and ethynodiol diacetate) 1/50-28: Each white tablet contains 1 mg of ethynodiol diacetate and 50 mcg of ethinyl estradiol, and the inactive ingredients include calcium acetate, calcium phosphate, corn starch, hydrogenated castor oil, and povidone. Each pink tablet in the Demulen (ethinyl estradiol and ethynodiol diacetate) 1/50-28 package is a placebo containing no active ingredients, and the inactive ingredients include calcium sulfate, corn starch, FD&C Red No. 3, FD&C Yellow No. 6, magnesium stearate, and sucrose.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Female Contraception.

DOSAGE AND ADMINISTRATION

Female: Contraception: Oral:

  • Schedule 1 (Sunday starter): Dose begins on first Sunday after onset of menstruation; if the menstrual period starts on Sunday, take first tablet that very same day. With a Sunday start, an additional method of contraception should be used until after the first 7 days of consecutive administration:
  • For 21-tablet package: 1 tablet/day for 21 consecutive days, followed by 7 days off of the medication; a new course begins on the 8th day after the last tablet is taken
  • For 28-tablet package: 1 tablet/day without interruption
  • Schedule 2 (Day-1 starter): Dose starts on first day of menstrual cycle taking 1 tablet/day:
  • For 21-tablet package: 1 tablet/day for 21 consecutive days, followed by 7 days off of the medication; a new course begins on the 8th day after the last tablet is taken
  • For 28-tablet package: 1 tablet/day without interruption

    If all doses have been taken on schedule and one menstrual period is missed, continue dosing cycle. If two consecutive menstrual periods are missed, pregnancy test is required before new dosing cycle is started.

    Missed doses monophasic formulations (refer to package insert for complete information):
  • One dose missed: Take as soon as remembered or take 2 tablets next day
  • Two consecutive doses missed in the first 2 weeks: Take 2 tablets as soon as remembered or 2 tablets next 2 days. An additional method of contraception should be used for 7 days after missed dose.
  • Two consecutive doses missed in week 3 or three consecutive doses missed at any time: An additional method of contraception must be used for 7 days after a missed dose:
  • Schedule 1 (Sunday starter): Continue dose of 1 tablet daily until Sunday, then discard the rest of the pack, and a new pack should be started that same day.
  • Schedule 2 (Day-1 starter): Current pack should be discarded, and a new pack should be started that same day.

Administer at the same time each day.

HOW SUPPLIED

Demulen (ethinyl estradiol and ethynodiol diacetate) 1/35: Each white Demulen (ethinyl estradiol and ethynodiol diacetate) 1/35 tablet is round in shape, with a debossed SEARLE on one side and 151 and design on the other side, and contains 1 mg of ethynodiol diacetate and 35 mcg of ethinyl estradiol. (Blue placebo tablets have a debossed SEARLE on one side and a "P" on the other side.)

Demulen (ethinyl estradiol and ethynodiol diacetate) 1/50: Each white Demulen (ethinyl estradiol and ethynodiol diacetate) 1/50 tablet is round in shape, with a debossed SEARLE on one side and 71 on the other side, and contains 1 mg of ethynodiol diacetate and 50 mcg of ethinyl estradiol. (Blue placebo tablets have a debossed SEARLE on one side and a "P" on the other side.)

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Cardiovascular: Arterial thromboembolism, cerebral hemorrhage, cerebral thrombosis, edema, hypertension, mesenteric thrombosis, myocardial infarction

Central nervous system: Depression, dizziness, headache, migraine, nervousness, premenstrual syndrome, stroke

Dermatologic: Acne, erythema multiforme, erythema nodosum, hirsutism, loss of scalp hair, melasma (may persist), rash (allergic)

Endocrine & metabolic: Amenorrhea, breakthrough bleeding, breast enlargement, breast secretion, breast tenderness, carbohydrate intolerance, lactation decreased (postpartum), glucose tolerance decreased, libido changes, menstrual flow changes, sex hormone-binding globulins (SHBG) increased, spotting, temporary infertility (following discontinuation), thyroid-binding globulin increased, triglycerides increased

Gastrointestinal: Abdominal cramps, appetite changes, bloating, cholestasis, colitis, gallbladder disease, jaundice, nausea, vomiting, weight gain/loss

Genitourinary: Cervical erosion changes, cervical secretion changes, cystitis-like syndrome, vaginal candidiasis, vaginitis

Hematologic: Antithrombin III decreased, folate levels decreased, hemolytic uremic syndrome, norepinephrine induced platelet aggregability increased, porphyria, prothrombin increased; factors VII, VIII, IX, and X increased

Hepatic: Benign liver tumors, Budd-Chiari syndrome, cholestatic jaundice, hepatic adenomas

Local: Thrombophlebitis

Ocular: Cataracts, change in corneal curvature (steepening), contact lens intolerance, optic neuritis, retinal thrombosis

Renal: Impaired renal function

Respiratory: Pulmonary thromboembolism

Miscellaneous: Hemorrhagic eruption

For additional information refer to Ethinyl Estradiol; Norethindrone.

Read the Demulen (ethinyl estradiol and ethynodiol diacetate) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Ethinyl estradiol: Substrate of CYP3A4 (major), 3A5-7 (minor); Inhibits CYP1A2 (weak), 2B6 (weak), 2C19 (weak), 3A4 (weak)

Acetaminophen: May increase plasma concentration of synthetic estrogens, possibly by inhibiting conjugation. Combination hormonal contraceptives may also decrease the plasma concentration of acetaminophen.

Acitretin: Interferes with the contraceptive effect of microdosed progestin-containing "minipill" preparations. The effect on other progestational contraceptives (eg, implants, injectables) is unknown.

Aminoglutethimide: May increase CYP metabolism of progestins leading to possible decrease in contraceptive effectiveness. Use of a nonhormonal contraceptive product is recommended.

Antibiotics (ampicillin, tetracycline): Pregnancy has been reported following concomitant use, however, pharmacokinetic studies have not shown consistent effects with these antibiotics on plasma concentrations of synthetic steroids. Use of a nonhormonal contraceptive product is recommended.

Anticoagulants: Combination hormonal contraceptives may increase or decrease the effects of coumarin derivatives. Combination hormonal contraceptives may also increase risk of thromboembolic disorders

Anticonvulsants (carbamazepine, felbamate, phenobarbital, phenytoin, topiramate): Increase the metabolism of ethinyl estradiol and/or some progestins, leading to possible decrease in contraceptive effectiveness. Use of a nonhormonal contraceptive product is recommended.

Ascorbic acid: Doses of ascorbic acid (vitamin C) 1 g/day have been reported to increase plasma concentration of synthetic estrogens by ~47%, possibly by inhibiting conjugation; clinical implications are unclear.

Atorvastatin: Atorvastatin increases the AUC for norethindrone and ethinyl estradiol.

Benzodiazepines: Combination hormonal contraceptives may decrease the clearance of some benzodiazepines (alprazolam, chlordiazepoxide, diazepam) and increase the clearance of others (lorazepam, oxazepam, temazepam)

Clofibric acid: Combination hormonal contraceptives may increase the clearance of clofibric acid.

Cyclosporine: Combination hormonal contraceptives may inhibit the metabolism of cyclosporine, leading to increased plasma concentrations; monitor cyclosporine levels

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of ethinyl estradiol. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

Griseofulvin: Griseofulvin may induce the metabolism of combination hormonal contraceptives causing menstrual changes; pregnancies have been reported. Use of barrier form of contraception is suggested while on griseofulvin therapy.

Morphine: Combination hormonal contraceptives may increase the clearance of morphine.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Nevirapine may decrease plasma levels of combination hormonal contraceptives; use of a nonhormonal contraceptive product is recommended. No data for delavirdine; incomplete data for efavirenz

Prednisolone: Ethinyl estradiol may inhibit the metabolism of prednisolone, leading to increased plasma concentrations.

Protease inhibitors: Amprenavir, lopinavir, nelfinavir, and ritonavir have been shown to decrease plasma levels of combination hormonal contraceptives; use of a nonhormonal contraceptive product is recommended. Indinavir has been shown to increase plasma levels of combination hormonal contraceptives. No data for saquinavir.

Rifampin: Rifampin increases the metabolism of ethinyl estradiol and some progestins (norethindrone) resulting in decreased contraceptive effectiveness and increased menstrual irregularities. Use of a nonhormonal contraceptive product is recommended.

Salicylic acid: Combination hormonal contraceptives may increase the clearance of salicylic acid.

Selegiline: Combination hormonal contraceptives may increase the serum concentration of selegiline.

Theophylline: Ethinyl estradiol may inhibit the metabolism of theophylline, leading to increased plasma concentrations.

Tricyclic antidepressants (amitriptyline, imipramine, nortriptyline): Metabolism may be inhibited by combination hormonal contraceptives, increasing plasma levels of antidepressant; use caution.

ETHANOL / NUTRITION / HERB INTERACTIONS

Food: CNS effects of caffeine may be enhanced if combination hormonal contraceptives are used concurrently with caffeine. Grapefruit juice increases ethinyl estradiol concentrations and would be expected to increase progesterone serum levels as well; clinical implications are unclear.

Herb/Nutraceutical: St John's wort may decrease the effectiveness of combination hormonal contraceptives by inducing hepatic enzymes. Avoid dong quai and black cohosh (have estrogen activity). Avoid saw palmetto, red clover, ginseng.

For additional information refer to Ethinyl Estradiol; Norethindrone.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Combination hormonal contraceptives do not protect against HIV infection or other sexually-transmitted diseases. The risk of cardiovascular side effects increases in women who smoke cigarettes, especially those who are >35 years of age; women who use combination hormonal contraceptives should be strongly advised not to smoke. Combination hormonal contraceptives may lead to increased risk of myocardial infarction, use with caution in patients with risk factors for coronary artery disease. May increase the risk of thromboembolism. Combination hormonal contraceptives may have a dose-related risk of vascular disease, hypertension, and gallbladder disease. Women with hypertension should be encouraged to use a nonhormonal form of contraception. The use of combination hormonal contraceptives has been associated with a slight increase in frequency of breast cancer, however, studies are not consistent. Combination hormonal contraceptives may cause glucose intolerance. Retinal thrombosis has been reported (rarely). Use with caution in patients with renal disease, conditions that may be aggravated by fluid retention, depression, or history of migraine. Not for use prior to menarche.

The minimum dosage combination of estrogen/progestin that will effectively treat the individual patient should be used. New patients should be started on products containing <50 mcg of estrogen per tablet.

For additional information refer to Ethinyl Estradiol; Norethindrone.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

Toxicity is unlikely following single exposures of excessive doses. Treatment following emesis and charcoal administration should be supportive and symptomatic..

For additional information refer to Ethinyl Estradiol; Norethindrone.

CONTRAINDICATIONS

Hypersensitivity to ethinyl estradiol, ethynodiol diacetate, or any component of the formulation; history of or current thrombophlebitis or venous thromboembolic disorders (including DVT, PE); active or recent (within 1 year) arterial thromboembolic disease (eg, stroke, MI); cerebral vascular disease, coronary artery disease, valvular heart disease with complications, severe hypertension; diabetes mellitus with vascular involvement; severe headache with focal neurological symptoms; known or suspected breast carcinoma, endometrial cancer, estrogen-dependent neoplasms, undiagnosed abnormal genital bleeding; hepatic dysfunction or tumor, cholestatic jaundice of pregnancy, jaundice with prior combination hormonal contraceptive use; major surgery with prolonged immobilization; heavy smoking ( 15 cigarettes/day) in patients >35 years of age; pregnancy.

For additional information refer to Ethinyl Estradiol; Norethindrone.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

MECHANISM OF ACTION — Combination hormonal contraceptives inhibit ovulation via a negative feedback mechanism on the hypothalamus, which alters the normal pattern of gonadotropin secretion of a follicle-stimulating hormone (FSH) and luteinizing hormone by the anterior pituitary. The follicular phase FSH and midcycle surge of gonadotropins are inhibited. In addition, combination hormonal contraceptives produce alterations in the genital tract, including changes in the cervical mucus, rendering it unfavorable for sperm penetration even if ovulation occurs. Changes in the endometrium may also occur, producing an unfavorable environment for nidation. Combination hormonal contraceptive drugs may alter the tubal transport of the ova through the fallopian tubes. Progestational agents may also alter sperm fertility.

For additional information refer to Ethinyl Estradiol; Norethindrone.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Report signs or symptoms of any of the following: Thromboembolic or thrombotic disorders including sudden severe headache or vomiting, disturbance of vision or speech, loss of vision, numbness or weakness in an extremity, sharp or crushing chest pain, calf pain, shortness of breath, severe abdominal pain or mass, mental depression or unusual bleeding. Discontinue taking the medication if you suspect you are pregnant or become pregnant.

For additional information refer to Ethinyl Estradiol; Norethindrone.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

Report signs or symptoms of any of the following: Thromboembolic or thrombotic disorders including sudden severe headache or vomiting, disturbance of vision or speech, loss of vision, numbness or weakness in an extremity, sharp or crushing chest pain, calf pain, shortness of breath, severe abdominal pain or mass, mental depression or unusual bleeding. Discontinue taking the medication if you suspect you are pregnant or become pregnant.

For additional information refer to Ethinyl Estradiol; Norethindrone.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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