ALYACEN 1/35(Norethindrone and Ethinyl Estradiol Tablets USP , 1 mg/0.035mg) DESCRIPTION Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. COMBINATION ORAL CONTRACEPTIVES The following product is a combination oral contraceptive containing the progestational compound norethindrone USP and the estrogenic compound ethinyl estradiol USP. ALYACEN 1/35: Each peach tablet contains 1 mg of norethindrone USP and 0.035 mg of ethinyl estradiol USP. Inactive ingredients include colloidal silicon dioxide, FD&C Yellow No. 6, anhydrous lactose, lactose monohydrate, magnesium stearate, pregelatinized starch and talc. Each light green tablet contains only inert ingredients, as follows: D&C Yellow No. 10, FD&C Blue No. 2, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch and talc. The chemical name for norethindrone USP is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one, for ethinyl estradiol USP is 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. Their structural formulas are as follows: Norethindrone USP Ethinyl estradiol USP CLINICAL PHARMACOLOGY COMBINATION ORAL CONTRACEPTIVES Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). INDICATIONS AND USAGE ALYACEN 1/35 is indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception. Oral contraceptives are highly effective. Table 1 lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates TABLE 1: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF TYPICAL USE AND THE FIRST YEAR OF PERFECT USE OF CONTRACEPTION AND THE PERCENTAGE CONTINUING USE AT THE END OF THE FIRST YEAR. UNITED STATES. % of Women Experiencing an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year3 Method (1) Typical Use1 (2) Perfect Use2 (3) (4) Chance4 85 85 Spermicides5 26 6 40 Periodic abstinence 25 63 Calendar 9 Ovulation Method 3 Sympto-Thermal6 2 Post-Ovulation 1 Withdrawal 19 4 Cap7 Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragm7 20 6 56 Condom8 Female (Reality) 21 5 56 Male 14 3 61 Pill 5 71 Progestin Only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera 0.3 0.3 70 Norplant and Norplant-2 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.1 100 Adapted from Hatcher et al, 1998, Ref. . 1Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 2 Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. 4 The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. 5 Foams, creams, gels, vaginal suppositories, and vaginal film. 6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. 7 With spermicidal cream or jelly. 8 Without spermicides CONTRAINDICATIONS Oral contraceptives should not be used in women who currently have the following conditions: •Thrombophlebitis or thromboembolic disorders •A past history of deep vein thrombophlebitis or thromboembolic disorders •Cerebral vascular or coronary artery disease •Known or suspected carcinoma of the breast •Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia •Undiagnosed abnormal genital bleeding •Cholestatic jaundice of pregnancy or jaundice with prior pill use •Hepatic adenomas or carcinomas •Known or suspected pregnancy WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke. The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes. Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from refs. 2 and 3 with the author’s permission). For further information, the reader is referred to a text on epidemiological methods. 1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS a. Myocardial Infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.4-10 The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.11 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older among women who use oral contraceptives. TABLE II: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE (Adapted from P.M. Layde and V. Beral, ref. # 12) Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.14-18 Oral contraceptives have been shown to increase blood pressure among users (see Section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. b. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.2,3,19-24 Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.25 The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.2 A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives.9 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.26 If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast feed or four weeks after a second trimester abortion. c. Cerebrovascular diseases Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.27-29 In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.30 The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.30 The attributable risk is also greater in older women.3 d. Dose-related risk of vascular disease from oral contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.31-33 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.14-16 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the activity of the progestogen used in the contraceptives. The activity and amount of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing 0.035 mg or less of estrogen. e. Persistence of risk of vascular disease There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.8 In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.34 However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens. 2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table III). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke, and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s.35 Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs. TABLE III: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44 No fertility control methods* 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker** 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker** 2.2 3.4 6.6 13.5 51.1 117.2 IUD** 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 *Deaths are birth-related **Deaths are method-related Adapted from H.W. Ory, ref. #35 3. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives. While there are conflicting reports, most studies suggest that use of oral contraceptives is not associated with an overall increase in the risk of developing breast cancer. Some studies have reported an increased relative risk of developing breast cancer particularly at a younger age. This increased relative risk has been reported to be related to duration of use. 38-44,79-89 A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them within the past ten years. This increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use.90 Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women.45-48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. 4. HEPATIC NEOPLASIA Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.50,51 Studies have shown an increased risk of developing hepatocellular carcinoma52-54,91 in oral contraceptive users. However, these cancers are extremely rare in the U.S. 5. OCULAR LESIONS There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. 6. ORAL CONTRACEPTIVE USE BEFORE OR DURING EARLY PREGNANCY Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.56,57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned,55,56,58,59 when taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued until pregnancy is ruled out. 7. GALLBLADDER DISEASE Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.62-64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. 8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.17 This effect has been shown to be directly related to estrogen dose.65 Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.17,66 However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. 9. ELEVATED BLOOD PRESSURE An increase in blood pressure has been reported in women taking oral contraceptives68 and this increase is more likely in older oral contraceptive users69 and with extended duration of use.61 Data from the Royal College of General Practitioners12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity. Women with a history of hypertension or hypertension-related diseases, or renal disease70 should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension between former and never users.68-71 10. HEADACHE The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause. 11. BLEEDING IRREGULARITIES Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent. 12. ECTOPIC PREGNANCY Ectopic as well as intrauterine pregnancy may occur in contraceptive failures. PRECAUTIONS 1. PHYSICAL EXAMINATION AND FOLLOW UP It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. 2. LIPID DISORDERS Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. 3. LIVER FUNCTION If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. 4. FLUID RETENTION Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 5. EMOTIONAL DISORDERS Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. 6. CONTACT LENSES Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 7. DRUG INTERACTIONS Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. A similar association though less marked has been suggested with barbiturates, phenylbutazone, phenytoin sodium, carbamazepine and possibly with griseofulvin, ampicillin and tetracyclines72. Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when coadministered due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.93 8. INTERACTIONS WITH LABORATORY TESTS Certain endocrine and liver function tests and blood components may be affected by oral contraceptives: 1.Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. 2.Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered. 3.Other binding proteins may be elevated in serum. 4.Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged. 5.Triglycerides may be increased. 6.Glucose tolerance may be decreased. 7.Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives. 9. CARCINOGENESIS See WARNINGS Section. 10. PREGNANCY Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS Sections. 11. NURSING MOTHERS Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combination oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use combination oral contraceptives but to use other forms of contraception until she has completely weaned her child. 12. PEDIATRIC USE Safety and efficacy of ALYACEN 1/35 have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. 13. SEXUALLY TRANSMITTED DISEASES Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. INFORMATION FOR THE PATIENT See Patient Labeling printed below. ADVERSE REACTIONS An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (See WARNINGS Section). •Thrombophlebitis and venous thrombosis with or without embolism •Arterial thromboembolism •Pulmonary embolism •Myocardial infarction •Cerebral hemorrhage •Cerebral thrombosis •Hypertension •Gallbladder disease •Hepatic adenomas or benign liver tumors The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related: •Nausea •Vomiting •Gastrointestinal symptoms (such as abdominal cramps and bloating) •Breakthrough bleeding •Spotting •Change in menstrual flow •Amenorrhea •Temporary infertility after discontinuation of treatment •Edema •Melasma which may persist •Breast changes: tenderness, enlargement, secretion •Change in weight (increase or decrease) •Change in cervical erosion and secretion •Diminution in lactation when given immediately postpartum •Cholestatic jaundice •Migraine •Rash (allergic) •Mental depression •Reduced tolerance to carbohydrates •Vaginal candidiasis •Change in corneal curvature (steepening) •Intolerance to contact lenses The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted: •Pre-menstrual syndrome •Cataracts •Changes in appetite •Cystitis-like syndrome •Headache •Nervousness •Dizziness •Hirsutism •Loss of scalp hair •Erythema multiforme •Erythema nodosum •Hemorrhagic eruption •Vaginitis •Porphyria •Impaired renal function •Hemolytic uremic syndrome •Acne •Changes in libido •Colitis •Budd-Chiari Syndrome OVERDOSAGE Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females. NON-CONTRACEPTIVE HEALTH BENEFITS The following non-contraceptive health benefits related to the use of combination oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg mestranol.73-78 Effects on menses: •increased menstrual cycle regularity •decreased blood loss and decreased incidence of iron deficiency anemia •decreased incidence of dysmenorrhea Effects related to inhibition of ovulation: •decreased incidence of functional ovarian cysts •decreased incidence of ectopic pregnancies Other effects: •decreased incidence of fibroadenomas and fibrocystic disease of the breast •decreased incidence of acute pelvic inflammatory disease •decreased incidence of endometrial cancer •decreased incidence of ovarian cancer. DOSAGE AND ADMINISTRATION To achieve maximum contraceptive effectiveness, ALYACEN 1/35 tablets  must be taken exactly as directed and at intervals not exceeding 24 hours.   ALYACEN 1/35  tablets are available in a blister pack which is preset for a Sunday Start. Day 1 Start is also available. 28- Day Regimen ( Sunday Start ) When taking ALYACEN 1/35, the first tablet should be taken on the first Sunday after menstruation begins. If period begins on Sunday, the first tablet should be taken that day. Take one active tablet daily for 21 days followed by one light green placebo tablet daily for 7 days. After 28 tablets have been taken, a new course is started the next day (Sunday). For the first cycle of a Sunday Start regimen, another method of contraception should be used until after the first 7 consecutive days of administration. If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in a row, the patient should continue taking one tablet every day until Sunday. On Sunday the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (“How to Take the Pill” section). 28-Day Regimen (Day 1 Start) The dosage of ALYACEN 1/35, for the initial cycle of therapy is one active tablet administered daily from the 1st through the 21st day of the menstrual cycle, counting the first day of menstrual flow as “Day 1” followed by one light green tablet daily for 7 days. Tablets are taken without interruption for 28 days. After 28 tablets have been taken, a new course is started the next day. If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers. If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. If the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills. Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed Patient Labeling (“How to Take the Pill” section). The use of ALYACEN 1/35 , for contraception may be initiated 4 weeks postpartum in women who elect not to breast feed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS for “Nursing Mothers.”) The possibility of ovulation and conception prior to initiation of medication should be considered. (See Discussion of Dose-Related Risk of Vascular Disease from Oral Contraceptives.) ADDITIONAL INSTRUCTIONS FOR ALL DOSING REGIMENS Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, nonfunctional causes should be borne in mind. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease. Use of oral contraceptives in the event of a missed menstrual period: 1.If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and oral contraceptive use should be discontinued until pregnancy is ruled out. 2.If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use HOW SUPPLIED ALYACEN 1/35 tablets are available in a blister pack (NDC 68462-394-84) containing 28 tablets, as follows: 21 peach, round, flat faced, beveled edged uncoated tablets debossed with ‘A1’ on one side (1 mg norethindrone USP and 0.035 mg ethinyl estradiol USP) and 7 light green, round, flat faced, beveled edged uncoated tablets debossed with ‘A2’ on one side containing inert ingredients. The blister packs are available in boxes of 3 (NDC 68462-394-29) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. http://whatsthedose.com/spl/68462-394.html 部分中文ALYACEN处方资料（仅供参考） 分类名称 一级分类：妇产科用药 二级分类：雌激素类及抗雌激素类药     药品英文名 Estrsdiol/Norethisterone 药品别名 诺更宁、诺康律、克龄蒙 药理作用 雌二醇主要由卵巢成熟卵泡分泌，具有如下作用： 1.促进女性性征和性器官的发育成熟。 2.维持性征，参与月经周期的形成，促使子宫内膜增殖变厚，宫颈黏液增多，并增强子宫平滑肌收缩。 3.较大剂量时可抑制下丘脑-垂体系统促性腺激素释放激素的分泌和抗催乳素作用。 4.抗雄性激素作用。 5.轻度水、钠潴留作用。 6.降血中胆固醇和增加骨骼钙沉积作用。 17-β雌二醇主要作用为调节和维持妇女正常平稳的雌激素生理水平。 本品不影响抗凝血酶因子Ⅲ，使血栓栓塞的危险降低。 可改善心血管功能，适用于糖尿病、肝病、心血管疾病及肥胖的患者。 诺坤复、诺康律、诺更宁系列产品的主要成分为微粒化天然人雌激素17β-雌二醇，其化学结构、生理作用及代谢途径均与卵巢产生的内源性17β雌二醇完全一致，其在人体内的代谢过程是自然的，所有代谢产物都是已知的，并且也是在人体内自然发生的。 甲基炔诺酮具有很强的孕激素作用，并有雄激素、雌激素和抗雌激素活性。与雌激素配合，周期性用于激素替代疗法。 克龄蒙是一种高效的雌激素-孕激素复方，其中含有孕激素醋酸环丙孕酮，有抗雄激素作用，可维持血清中脂蛋白水平的稳定，有助于预防心血管系统动脉硬化的发生，可保护子宫内膜，减少了内膜增生的危险性。本药能迅速缓解因激素缺乏而引起的更年期症状，还对皮肤和黏膜退化(尤其是泌尿生殖的黏膜)有明显改善作用，并对因雌激素缺乏而引起的骨质疏松有预防作用。 药动学 用雌二醇贴片后血浆内雌二醇水平迅速上升，达峰时间在22～24h之间，血中雌二醇浓度在150pmol/L左右，可维持3～7天。停用后，雌二醇浓度在24h内恢复至用药前水平。 苯甲酸雌二醇注射液在血液内，部分与β球蛋白结合，游离的雌二醇被组织利用。部分被肝脏破坏，或经胆汁排泄，再被肠道吸收，形成肠肝循环，其代谢产物多与硫酸或葡萄糖醛酸结合成酯后从尿中排出。 适应证 雌激素缺乏综合征。 制剂注释与选择： 1.17-β雌二醇凝胶凝胶剂经皮吸收进入体内，不经肝肠循环，无首关效应，避免了对肝脏的损害。适用于肝功能不良者。 2.雌二醇皮肤贴膜剂 制剂中活性药膜层可通过皮肤直接向体循环释放药物，从而避免了口服药物的肝脏首关效应及其引发的治疗时的不良反应。得美素提供的雌激素可以在血中达到一个持续、均匀而稳定的生理浓度。缓释贴膜剂可3～4天用药一次。周效控释贴膜每周用药一次即可。 3.诺坤复、诺康律、诺更宁采用微粒化技术保证了其口服后可迅速高效地吸收。采用独特的日历盘式包装，每个日历盘包装含28片药片。 一天1片，使用方便，有助于提高服药的顺应性，可避免因中断治疗而出现的症状反复。 (1)诺更宁：本品为17β-雌二醇/醋酸炔诺酮二相片，每片含雌二醇2mg(为半水合物)和醋酸炔诺酮1mg。适用于绝经后妇女补充雌激素，治疗雌激素缺乏综合征，使月经周期停止。 (2)诺康律：本品为17β-雌二醇/醋酸炔诺酮三相片，蓝色片剂含雌二醇2mg，12片；白色片剂含雌二醇2mg和醋酸炔诺酮1mg，10片；红色片剂含雌二醇1mg，6片。 适用于围绝经期妇女补充雌激素，治疗雌激素缺乏综合征，使月经周期规律化。 4.克龄蒙 本药是一种雌-孕激素复方制剂，每一天历包装含有11片戊酸雌二醇，每片含戊酸雌二醇2mg；10片戊酸雌二醇与醋酸环丙孕酮复方片剂，每片含戊酸雌二醇2mg，醋酸环丙孕酮1mg。 禁忌证 对本品成分高度过敏者禁用。子宫、阴道或乳房有激素依赖性肿瘤、子宫内膜异位症者禁用。严重肝肾功能异常、既往或现有肝脏肿瘤、既往妊娠期间有过持续性瘙痒、妊娠期疱疹史、妊娠期耳硬化症恶化，血栓栓塞性疾病、镰状细胞性贫血、伴有血管病变的严重糖尿病、脂肪代谢先天异常、。Dubin-Johnson综合征、Rotor综合征、代谢性卟啉症患者禁用。孕妇及正在哺乳的妇女禁用。 注意事项 口服制剂用量不宜过大。 不良反应 可能出现轻度胃肠不适。贴片处皮肤可能有轻度发红或瘙痒，偶有皮疹。 可能有乳腺增大、乳房肿胀疼痛或出现分泌物、不规则流血、月经改变或闭经；偶见恶心、呕吐、腹胀，水肿、皮肤反应、头痛、偏头痛、胆石症、气喘、脱发，发生胆汁郁积症及胰腺炎、皮肤黄褐斑、舞蹈症。角膜曲度可能发生改变，不能戴隐形眼镜；性欲改变及卟啉症恶化、水钠潴留等。罕见静脉血栓。乳腺癌、子宫内膜癌也有报道。 用法用量 1.用于绝经期综合征、功能性子宫出血、原发性闭经、前列腺癌及退乳，雌激素水平低的替代疗法(需个体化剂量)。 (1)口服 ①戊酸雌二醇片：每次服药2mg片，每天1次，饭后服用，或遵医嘱。药片应与水一起吞服。每经过21天的治疗后，必须停服此药至少一周。治疗过程中，根据患者情况，可将补佳乐剂量减至每天服用1mg。 ②诺坤复、诺更宁：采用独特的日历盘式包装，一天1片。 ③克龄蒙：服药时，把日历贴纸取出，贴在药片包装中央，使开始服药的日期对准标有“Start”(开始)字样。 服药自标有“Start”(开始)字样处开始，按箭头方向服用，每天1片，直至服完21片。药片宜整片用水送服，停药7天后继续服用。 (2)外用： ①17-β雌二醇凝胶：每天将凝胶2.5g涂布于双臀、肩颈、腹壁、大腿皮肤上，药物经皮肤吸收。已绝经者每次1.25～2.5g(每半剂量尺相当于1.25g，含雌二醇0.75g)，每天1次，连用25天，停用5天；有子宫者应与孕酮合用，每天100mg，连用25天，停用5天；尚未绝经者，于周期第5天开始使用，每天1.25～2.5g，连用25天，于用药后的14天加用孕酮每天200～300mg，共用12天。 ②雌二醇控释贴片(周效)：每周1次，可采用连续治疗方案或连用3周停药1周方案，应每月常规联用10～12天的孕激素。如采用连续治疗方案可在任意时间开始使用孕激素。如采用连用3周停药1周方案，则应在周期的最后10～12天使用孕激素。 ③伊尔：每周用药1次，每片含雌二醇2.5mg，贴在下腹部或臀部皮肤上，共3次，停用1周。在最后5天每天服安宫黄体酮，每次4mg。 ④雌二醇控释贴片：每次1片，每周用2次，可以连续使用，也可连用3周，停药1周。连续使用者应每天连用一定剂量的孕激素，周期使用者应在周期的最后10天联用一定剂量的孕激素。 ⑤伊司乐：每次1片，每周用2次，连用3周，停药1周，最后5天加安宫黄体酮，每天4～5mg。肌注苯甲酸雌二醇注射液：一次1～2mg，一周2～3次。 2.用于功能性子宫出血 肌注：苯甲酸雌二醇注射液：1mg～2mg，至血净后酌情减量，后期择日用黄体酮撤退。 3.用于退奶 肌注：苯甲酸雌二醇注射液：每天2mg，不超过3天后减量或改小量口服药至生效。 4.用于围绝经期妇女生理性补充雌激素 (1)口服：诺康律：每天1片，有月经的妇女在月经第5天开始服第1片(由蓝片开始)。其他妇女可以在任何一天开始服药。开始12天服用蓝片，其后10天服用白片，最后6天服用红片。 ①开始用激素替代疗法前，应作全面彻底的内科和妇科检查，特别是血压测量，乳房、腹部及妇科检查。用药期间每6个月应进行检查。在绝经后妇女用雌激素替代疗法有引发子宫内膜过度增生或子宫内膜癌的危险，故需每年检查1次。 ②口服制剂：患者在一天内的具体服药时间不拘，但如已选定某一特定时间(如早饭后)，则每天应在相同时间内服用。如果忘记按时服药，则应在12h内补服上。使用雌激素替代疗法的妇女胆囊炎的发病率升高。用药期间如果出现下列症状需立即停药：第一次发生偏头痛或频发少见的严重头痛、突发性感觉障碍、血栓性静脉炎或血栓栓塞的首发指征、胸痛、紧缩感、癫痫发作次数增加、待定的手术(提前6周)、固定术(如事故后)、发生黄疸、全身瘙痒、血压 升高、妊娠。 ③有子宫肌瘤、心脏病、癫痫、糖尿病及高血压患者慎用。有完整子宫的妇女如出现原因不明的阴道流血或曾用非对抗雌激素治疗过，应特别注意检查是否有子宫内膜过度刺激或恶变。 ④急慢性肝病或有肝病史的妇女，用药期间应定期检查肝功能。有静脉血栓栓塞性疾病应定期检查血液凝固的指标。 ⑤接受抗高血压治疗或有癫痫、高血压、偏头痛、糖尿病、气喘病或心力衰竭、静脉曲张、多发性硬化、卟啉症、手足搐搦、小舞蹈病、静脉炎史患者应在监护下用药。 ⑥少数良性或极少数恶性肝脏肿瘤患者，服用激素类药物后其中个别病例可能发生危及生命的腹腔内出血。 因此，若发生异常的上腹部症状，且短时间内不自行消失，应告诉医生。 (2)继发性闭经治疗前，应排除催乳素垂体瘤的可能。 ①17-β雌二醇凝胶含少量乙醇，个别患者可能有局部刺激感，不影响药效。 ②17-β雌二醇。 药物相应作用 本品与巴比妥、保泰松、利福平、酰胺咪嗪等肝药酶诱导剂合用可增加本品的代谢，降低疗效。 本品与口服降糖药或胰岛素合用，后者的剂量可能需要调整。 专家点评 雌二醇/炔诺酮的制剂，诺坤复、诺康律、诺更宁系列产品的主要成分为微粒化天然人雌激素17β-雌二醇，其化学结构、生理作用及代谢途径均与卵巢产生的内源性17β雌二醇完全一致，其在人体内的代谢过程是自然的，所有代谢产物都是已知的，并且也是在人体内自然发生的。甲基炔诺酮具有很强的孕激素作用，并有雄激素、雌激素和抗雌激素活性。与雌激素配合，周期性用于激素替代疗法。每天在相同时间内服用本药是起得好疗效的关键。 --------------------------------------------------------------- 产地国家: 美国 原产地英文商品名: ALYACEN 1-35 (1-0.035)MG/TAB 28TABS/BOX 原产地英文药品名: NORETHINDRONE-ETHINYL ESTRADIOL 中文参考商品译名: ALYACEN 1-35 (1-0.035)毫克/片 28片/盒 中文参考药品译名: 炔诺酮-乙炔雌二醇 生产厂家中文参考译名: GLENMARK GENERICS 生产厂家英文名: GLENMARK GENERICS