Norethindrone acetate and Ethinyl estradiol

Norethindrone acetate and Ethinyl estradiol
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]

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Overview

Norethindrone acetate and Ethinyl estradiol is a contraceptive agent that is FDA approved for the treatment of acne-contraception, contraception, moderate to severe abnormal vasomotor function in menopause and for prophylaxis of postmenopausal osteoporosis, in women with an intact uterus. Common adverse reactions include abdominal cramps, abdominal pain, bloating symptom, nausea headache, break-through bleeding, pain of breast.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Contraception

• Norethindrone acetate and ethinyl estradiol tablets, USP are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

• Oral contraceptives are highly effective. Table I 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.

• Dosing information

• The tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in three rows of seven tablets each, with the days of the week appearing on the tablet dispenser above the first row of tablets.

• Note: Each tablet dispenser has been preprinted with the days of the week, starting with Sunday, to facilitate a Sunday-Start regimen. Six different day label strips have been provided with the Detailed Patient & Brief Summary Patient Package Insert in order to accommodate a Day-1 Start regimen. If the patient is using the Day-1 Start regimen, she should place the self-adhesive day label strip that corresponds to her starting day over the preprinted days.

• Important: The patient should be instructed to use an additional method of protection until after the first week of administration in the initial cycle when utilizing the Sunday-Start regimen.

• The possibility of ovulation and conception prior to initiation of use should be considered.

• Dosage and Administration for 21-Day Dosage Regimen

• To achieve maximum contraceptive effectiveness, norethindrone acetate and ethinyl estradiol tablets, USP should be taken exactly as directed and at intervals not exceeding 24 hours.

• Norethindrone acetate and ethinyl estradiol tablets, USP provide the patient with a convenient tablet schedule of “3 weeks on –1 week off.” Two dosage regimens are described, one of which may be more convenient or suitable than the other for an individual patient. For the initial cycle of therapy, the patient begins her tablets according to the Day-1 Start or Sunday-Start regimen. With either regimen, the patient takes one tablet daily for 21 consecutive days followed by one week of no tablets.

• A. Sunday-Start Regimen:

• The patient begins taking tablets from the top row on the first Sunday after menstrual flow begins. When menstrual flow begins on Sunday, the first tablet is taken on the same day. The last tablet in the dispenser will then be taken on a Saturday, followed by no tablets for a week (7 days). For all subsequent cycles, the patient then begins a new 21-tablet regimen on the eighth day, Sunday, after taking her last tablet. Following this regimen, of 21 days on–7 days off, the patient will start all subsequent cycles on a Sunday.

• B. Day-1 Start Regimen:

• The first day of menstrual flow is Day 1. The patient places the self-adhesive day label strip that corresponds to her starting day over the preprinted days on the tablet dispenser. She starts taking one light green tablet daily, beginning with the first light green tablet in the top row. The patient completes her 21-tablet regimen when she has taken the last tablet in the tablet dispenser. She will then take no tablets for a week (7 days). For all subsequent cycles, the patient begins a new 21-tablet regimen on the eighth day after taking her last tablet, again starting with the first tablet in the top row after placing the appropriate day label strip over the preprinted days on the tablet dispenser. Following this regimen of 21 days on–7 days off, the patient will start all subsequent cycles on the same day of the week as the first course. Likewise, the interval of no tablets will always start on the same day of the week.

• Tablets should be taken regularly with a meal or at bedtime. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule.

Acne-Contraception

• Dosing information

• 1 tablet ORALLY daily for 21 consecutive days followed by 1 week of no tablets.

Menopause - Moderate to severe abnormal vasomotor function

• Dosing information

• Femhrt(R), 1 tablet ORALLY daily; initiate therapy at the lowest effective dose and for the shortest duration consistent with treatment goals and risks.

Postmenopausal osteoporosis, In women with an intact uterus; Prophylaxis

• Dosing information

• Femhrt(R), 1 tablet ORALLY daily; initiate therapy at the lowest effective dose and for the shortest duration consistent with treatment goals and risks.

Noncontraceptive health benefits=

• The following non-contraceptive health benefits related to the use of 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 of mestranol (79 to 84).

• 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

• Effects from long-term use:

• 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

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

• There is limited information regarding Off-Label Guideline-Supported Use of Norethindrone acetate and Ethinyl estradiol tablet in adult patients.

Non–Guideline-Supported Use

• There is limited information regarding Off-Label Non–Guideline-Supported Use of Norethindrone acetate and Ethinyl estradiol tablet in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Acne - Contraception

• Dosing information

• 15 years of age and older and after menarche has begun, 1 tablet ORALLY daily for 21 consecutive days followed by 1 week of no tablets

Contraception

• Dosing information

• after menarche has begun, 1 tablet ORALLY daily for 21 consecutive days followed by 1 week of no tablets

• Safety and efficacy of femhrt(R) not established. Use of Junel(R), Loestrin(R), Microgestin(R) or Tri-Legest(R) for contraception before menarche is not indicated.

• Safety and efficacy of Tri-Legest(R) for acne in children less than 15 years of age not established

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

• There is limited information regarding Off-Label Guideline-Supported Use of Norethindrone acetate and Ethinyl estradiol tablet in pediatric patients.

Non–Guideline-Supported Use

• There is limited information regarding Off-Label Non–Guideline-Supported Use of Norethindrone acetate and Ethinyl estradiol tablet in pediatric patients.

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

• 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 References 8 and 9 with the author's permission). For further information, the reader is referred to a text on epidemiological methods.

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. 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. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Table II) among women who use oral contraceptives.

• Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity (19). In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (20 to 24). Oral contraceptives have been shown to increase blood pressure among users. 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 non-users 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. 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. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.

• A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives (15,32). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (15,32). 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 to six weeks after delivery in women who elect not to breast feed.

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, while smoking interacted to increase the risk for hemorrhagic strokes (33 to 35).

• 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. 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. The attributable risk is also greater in older women.

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 (37 to 39). A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. 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 progestin and the nature of the progestin used in the contraceptives. The amount and activity 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 oral contraceptive, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest dose of estrogen which produces satisfactory results for the patient.

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 to 49 years who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups. 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. However, both studies were performed with oral contraceptive formulations containing 50 mcg 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 a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.

• Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (Porter JB, Hunter J, Jick H, et al. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985;66:1-4; and Porter JB, Hershel J, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987;70:29-32), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. 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 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.

• Therefore, the Committee recommended that the benefits of 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 the lowest possible dose formulation that is effective.

Carcinoma of the Reproductive Organs

• Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. Most of the studies on breast cancer and oral contraceptive use report that the use of oral contraceptives is not associated with an increase in the risk of developing breast cancer. Some studies have reported an increased risk of developing breast cancer in certain subgroups of oral contraceptive users, but the findings reported in these studies are not consistent.

• 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. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

• In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause and effect relationship has not been established.

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. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.

• Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S., and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

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.

Oral Contraceptive Use Before and During Early Pregnancy

• Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned 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 if pregnancy is confirmed.

Gallbladder Disease

• Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

Carbohydrate and Lipid Metabolic Effects

• Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed 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.

Elevated Blood Pressure

• An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens.

• Women with a history of hypertension or hypertension-related diseases or renal disease 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 among ever and never users.

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.

Bleeding Irregularities

• Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Non-hormonal 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.

Precautions

• 1. Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

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.

Lipid Disorders

• Women who are being treated for hyperlipidemia 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.

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.

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.

Emotional Disorders

• Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

Contact Lenses

• Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

Adverse Reactions

Clinical Trials Experience

• An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section):

• Thrombophlebitis
• Arterial thromboembolism
• Pulmonary embolism
• Myocardial infarction
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors

• There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed:

• Mesenteric thrombosis
• Retinal thrombosis

• 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
• Budd-Chiari syndrome
• Acne
• Changes in libido
• Colitis

Postmarketing Experience

There is limited information regarding Norethindrone acetate and Ethinyl estradiol Postmarketing Experience in the drug label.

Drug Interactions

Effects of Other Drugs on Oral Contraceptives

Rifampin

• Metabolism of both norethindrone and ethinyl estradiol is increased by rifampin. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin.

Anticonvulsants

• Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine, have been shown to increase the metabolism of ethinyl estradiol and/or norethindrone, which could result in a reduction in contraceptive effectiveness.

Troglitazone

• Administration of troglitazone with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both by approximately 30%, which could result in a reduction in contraceptive effectiveness.

Antibiotics

• Pregnancy while taking oral contraceptives has been reported when the oral contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.

Atorvastatin

• Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively.

Other

• Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding has been suggested with phenylbutazone.

Effects of Oral Contraceptives on Other Drugs

• Oral contraceptive combinations containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives.

Interactions with Laboratory Tests

Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:

• Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
• 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.
• Other binding proteins may be elevated in serum.
• 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.
• Triglycerides may be increased.
• Glucose tolerance may be decreased.
• 8Serum 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Oral Contraceptive Use Before and During Early Pregnancy

• Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (61 to 63). Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned (61,62,64,65) 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 if pregnancy is confirmed.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Norethindrone acetate and Ethinyl estradiol in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Norethindrone acetate and Ethinyl estradiol during labor and delivery.

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, 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 oral contraceptives but to use other forms of contraception until she has completely weaned her child.

Pediatric Use

• Safety and efficacy of norethindrone acetate and ethinyl estradiol tablets 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.

Geriatic Use

There is no FDA guidance on the use of Norethindrone acetate and Ethinyl estradiol in geriatric settings.

Gender

There is no FDA guidance on the use of Norethindrone acetate and Ethinyl estradiol with respect to specific gender populations.

Race

There is no FDA guidance on the use of Norethindrone acetate and Ethinyl estradiol with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Norethindrone acetate and Ethinyl estradiol in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Norethindrone acetate and Ethinyl estradiol in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Norethindrone acetate and Ethinyl estradiol in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Norethindrone acetate and Ethinyl estradiol in patients who are immunocompromised.

Administration and Monitoring

Administration

• The tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in three rows of seven tablets each, with the days of the week appearing on the tablet dispenser above the first row of tablets.

• Note: Each tablet dispenser has been preprinted with the days of the week, starting with Sunday, to facilitate a Sunday-Start regimen. Six different day label strips have been provided with the Detailed Patient & Brief Summary Patient Package Insert in order to accommodate a Day-1 Start regimen. If the patient is using the Day-1 Start regimen, she should place the self-adhesive day label strip that corresponds to her starting day over the preprinted days.

• Important: The patient should be instructed to use an additional method of protection until after the first week of administration in the initial cycle when utilizing the Sunday-Start regimen.

• The possibility of ovulation and conception prior to initiation of use should be considered.

Dosage and Administration for 21-Day Dosage Regimen

• To achieve maximum contraceptive effectiveness, norethindrone acetate and ethinyl estradiol tablets, USP should be taken exactly as directed and at intervals not exceeding 24 hours.

• Norethindrone acetate and ethinyl estradiol tablets, USP provide the patient with a convenient tablet schedule of “3 weeks on –1 week off.” Two dosage regimens are described, one of which may be more convenient or suitable than the other for an individual patient. For the initial cycle of therapy, the patient begins her tablets according to the Day-1 Start or Sunday-Start regimen. With either regimen, the patient takes one tablet daily for 21 consecutive days followed by one week of no tablets.

A. Sunday-Start Regimen:

• The patient begins taking tablets from the top row on the first Sunday after menstrual flow begins. When menstrual flow begins on Sunday, the first tablet is taken on the same day. The last tablet in the dispenser will then be taken on a Saturday, followed by no tablets for a week (7 days). For all subsequent cycles, the patient then begins a new 21-tablet regimen on the eighth day, Sunday, after taking her last tablet. Following this regimen, of 21 days on–7 days off, the patient will start all subsequent cycles on a Sunday.

B. Day-1 Start Regimen:

• The first day of menstrual flow is Day 1. The patient places the self-adhesive day label strip that corresponds to her starting day over the preprinted days on the tablet dispenser. She starts taking one light green tablet daily, beginning with the first light green tablet in the top row. The patient completes her 21-tablet regimen when she has taken the last tablet in the tablet dispenser. She will then take no tablets for a week (7 days). For all subsequent cycles, the patient begins a new 21-tablet regimen on the eighth day after taking her last tablet, again starting with the first tablet in the top row after placing the appropriate day label strip over the preprinted days on the tablet dispenser. Following this regimen of 21 days on–7 days off, the patient will start all subsequent cycles on the same day of the week as the first course. Likewise, the interval of no tablets will always start on the same day of the week.

• Tablets should be taken regularly with a meal or at bedtime. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule.

Special Notes on Administration

• Menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after discontinuing medication. If spotting occurs while on the usual regimen of one tablet daily, the patient should continue medication without interruption.

• If the patient forgets to take one or more light green tablets, the following is suggested:

• One tablet is missed

• take tablet as soon as remembered
• take next tablet at the regular time

• Two consecutive tablets are missed (week 1 or week 2)

• take two tablets as soon as remembered
• take two tablets the next day
• use another birth control method for seven days following the missed tablets

• Two consecutive tablets are missed (week 3)

• Sunday-Start Regimen:

• take one tablet daily until Sunday
• discard remaining tablets
• start new pack of tablets immediately (Sunday)
• use another birth control method for seven days following missed tablets

• Day-1 Start Regimen:

• discard remaining tablets
• start new pack of tablets that same day
• use another birth control method for seven days following missed tablets

• Three (or more) consecutive tablets are missed

• Sunday-Start Regimen:

• take one tablet daily until Sunday
• discard remaining tablets
• start new pack of tablets immediately (Sunday)
• use another birth control method for seven days following missed tablets

• Day-1 Start Regimen:

• discard remaining tablets
• start new pack of tablets that same day
• use another birth control method for seven days following missed tablets

• The possibility of ovulation occurring increases with each successive day that scheduled light green tablets are missed. While there is little likelihood of ovulation occurring if only one light green tablet is missed, the possibility of spotting or bleeding is increased. This is particularly likely to occur if two or more consecutive light green tablets are missed.

• In the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from a new tablet dispenser on the next Sunday or the first day (Day-1), depending on her regimen. Persistent bleeding which is not controlled by this method indicates the need for reexamination of the patient, at which time nonfunctional causes should be considered.

• Use of Oral Contraceptives in the Event of a Missed Menstrual Period

• If the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period and oral contraceptives should be withheld until pregnancy has been ruled out.
• If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

• After several months on treatment, bleeding may be reduced to a point of virtual absence. This reduced flow may occur as a result of medication, in which event it is not indicative of pregnancy.

Monitoring

• Women with a history of hypertension or hypertension-related diseases or renal disease (76) 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 (75), and there is no difference in the occurrence of hypertension among ever and never users (74,76,77).

• Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

• 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.

IV Compatibility

There is limited information regarding the compatibility of Norethindrone acetate and Ethinyl estradiol and IV administrations.

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.

Pharmacology

There is limited information regarding Norethindrone acetate and Ethinyl estradiol Pharmacology in the drug label.

Mechanism of Action

• 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).

Structure

• Norethindrone acetate and ethinyl estradiol tablets, USP are progestogen-estrogen combinations.

• Norethindrone acetate and ethinyl estradiol tablets, USP provide a continuous dosage regimen consisting of 21 oral contraceptive tablets.

• Each light green tablet contains norethindrone acetate (17 alpha-ethinyl-19-nortestosterone acetate), 1.5 mg; ethinyl estradiol (17 alpha-ethinyl-1,3,5(10)-estratriene-3, 17 beta-diol), 0.03 mg. Also contains colloidal silicon dioxide, compressible sugar, croscarmellose sodium, D&C Yellow #10 aluminum lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol 400, polyethylene glycol 8000, pregelatinized starch, sodium lauryl sulfate and Vitamin E.

• The structural formulas are as follows:

Pharmacodynamics

There is limited information regarding Norethindrone acetate and Ethinyl estradiol Pharmacodynamics in the drug label.

Pharmacokinetics

• The pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been characterized; however, the following pharmacokinetic information regarding norethindrone acetate and ethinyl estradiol is taken from the literature.

Absorption

• Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone (1). Norethindrone acetate and ethinyl estradiol are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol (1 to 3).

Distribution

• Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg (1 to 3). Plasma protein binding of both steroids is extensive (> 95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin (4).

Metabolism

• Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites (5). A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation (6).

Excretion

• Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites (5,6). Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg) (1 to 3).

Special Population

Race

• The effect of race on the disposition of norethindrone acetate and ethinyl estradiol tablets have not been evaluated.

Renal Insufficiency

• The effect of renal disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.

Hepatic Insufficiency

• The effect of hepatic disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function.

Drug-Drug Interactions

• Numerous drug-drug interactions have been reported for oral contraceptives. A summary of these is found under PRECAUTIONS, Drug Interactions.

Nonclinical Toxicology

There is limited information regarding Norethindrone acetate and Ethinyl estradiol Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Norethindrone acetate and Ethinyl estradiol Clinical Studies in the drug label.

How Supplied

• Gildess® 1.5/30 (21 Tablets) (norethindrone acetate 1.5 mg and ethinyl estradiol 0.03 mg tablets, USP) is packaged in cartons of six tablet dispensers. Each tablet dispenser contains 21 light green, round, film-coated tablets debossed “93” on one side and “914”on the other side.

• Blister pack tablet dispenser NDC 0603-7606-02.
• Boxes of 6 tablet dispensers NDC 0603-7606-15.

Storage

• Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Images

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Patient Counseling Information

• Oral contraceptives, also known as "birth control pills" or "the pill," are taken to prevent pregnancy and, when taken correctly, have a failure rate of about 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy.

• For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you:

• Smoke
• Have high blood pressure, diabetes, high cholesterol
• Have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, or malignant or benign liver tumors.

• You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding.

Precautions with Alcohol

• Alcohol-Norethindrone acetate and Ethinyl estradiol tablet interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Loestrin 1/20 Loestrin 1.5/30 Junel 1/20, Junel 1.5/30, Microgestin 1/20, Microgestin 1.5/30, Femhrt 1/5, Femhrt Lo.

Look-Alike Drug Names

There is limited information regarding Norethindrone acetate and Ethinyl estradiol Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.