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Generic Name: norethindrone acetate and ethinyl estradiol and ferrous fumarate Dosage Form: tablets. Medically reviewed by Drugs. Last updated on Oct 22, The ferrous fumarate tablets are present to facilitate ease of drug administration via a day regimen, are non-hormonal, and do not serve any therapeutic purpose.
Also contains acacia, lactose monohydrate, magnesium stearate, corn starch, sucrose and talc. Each brown tablet contains microcrystalline cellulose, ferrous fumarate, magnesium stearate, povidone, sodium starch glycolate, corn starch and talc.
The ferrous fumarate tablets do not serve any therapeutic purpose. 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.
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 undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides ing 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 P Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa.
Ethinyl estradiol may undergo enterohepatic circulation 6. 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. 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.
Hailey fe 1/20 - clinical pharmacology
However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function. Numerous drug-drug interactions have been reported for oral contraceptives. 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. Cervical Cap with spermicidal cream or jelly nulliparous parous. 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 ificantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes.
Hailey fe 1/20
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.
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 10 to The risk is very low under the age of 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 ing 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 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism 20 to 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. 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.
Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped 8. A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives 15, The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions 15, 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 breastfeed. Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events thrombotic and hemorrhagic strokesalthough, in general, the risk is greatest among older greater than 35 yearshypertensive 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 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.
The attributable risk is also greater in older women 9.
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A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease 37 to A decline in serum high-density lipoproteins HDL has been reported with many progestational agents 20 to 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 for the patient. 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.
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.