Norgestrel/Ethinyl estradiol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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Black Box Warning
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TITLE
See full prescribing information for complete Boxed Warning.
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.
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Overview
Norgestrel/Ethinyl estradiol is an Estrogen that is FDA approved for the {{{indicationType}}} of prevention of pregnancy in women who elect to use this product as a method of contraception. There is a Black Box Warning for this drug as shown here. Common adverse reactions include {{{adverseReactions}}}.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Prevention of Pregnancy
- Indication
- Cryselle® (norgestrel and ethinyl estradiol tablets USP), 0.3 mg/0.03 mg 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 and the IUD, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
- Dosing information
- To achieve maximum contraceptive effectiveness, Cryselle® must be taken exactly as directed and at intervals not exceeding 24 hours. The dosage of Cryselle® is one white tablet daily for 21 consecutive days, followed by one light-green inert tablet daily for 7 consecutive days, according to prescribed schedule. It is recommended that tablets be taken at the same time each day, preferably after the evening meal or at bedtime.
- During the first cycle of medication, the patient is instructed to begin taking Cryselle® on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first tablet (white) is taken that day. One white tablet should be taken daily for 21 consecutive days followed by one light-green inert tablet daily for 7 consecutive days.
- Withdrawal bleeding should usually occur within three days following discontinuation of white tablets. During the first cycle, contraceptive reliance should not be placed on Cryselle® until a white tablet has been taken daily for 7 consecutive days. The possibility of ovulation and conception prior to initiation of medication should be considered.
- The patient begins her next and all subsequent 28 day courses of tablets on the same day of the week (Sunday) on which she began her first course, following the same schedule: 21 days on white tablets – 7 days on light-green inert tablets. If in any cycle the patient starts tablets later than the proper day, she should protect herself by using another method of birth control until she has taken a white tablet daily for 7 consecutive days.
- If spotting or breakthrough bleeding occurs, the patient is instructed to continue on the same regimen. This type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her physician.
- Although the occurrence of pregnancy is highly unlikely if Cryselle® is taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. If the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken before the medication is resumed. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.
- For additional patient instructions regarding missed pills, see the "WHAT TO DO IF YOU MISS PILLS" section in the DETAILED PATIENT LABELING below.
- Any time the patient misses two or more white tablets, she should also use another method of contraception until she has taken a white tablet daily for seven consecutive days. If the patient misses one or more light-green tablets, she is still protected against pregnancy provided she begins taking white tablets again on the proper day. If breakthrough bleeding occurs following missed white tablets, it will usually be transient and of no consequence. While there is little likelihood of ovulation occurring if only one or two tablets are missed, the possibility of ovulation increases with each successive day that scheduled white tablets are missed.
- In the nonlactating mother, Cryselle® may be initiated postpartum, for contraception. When the tablets are administered in the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS concerning thromboembolic disease). It is to be noted that early resumption of ovulation may occur if Parlodel® (bromocriptine mesylate) has been used for the prevention of lactation.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cryselle in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cryselle in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy of norgestrel and ethinyl estradiol tablets have been established in women of reproductive age.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cryselle in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cryselle in pediatric patients.
Contraindications
Oral contraceptives should not be used in women with any of 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
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TITLE
See full prescribing information for complete Boxed Warning.
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.
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The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, gallbladder disease, and hypertension, 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 based principally 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 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. 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. 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 nonsmokers over the age of 40 (TABLE 2) among women who use oral contraceptives.
TABLE : CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE
TABLE 2 Image
Adapted from P.M. Layde and V. Beral, Lancet, 1:541-546, 1981.
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. 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 factor
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. 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. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. 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, or a midtrimester pregnancy termination
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.
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 nonsmokers 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. 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 progestogen and the nature and absolute amount of progestogen used in the contraceptive. The 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 less than 50 mcg 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 to 49 years who had used oral contraceptives for five 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 micrograms or higher of estrogens
2. Estimates of Mortality From Oral 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 3). 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 less than 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, 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 nonsmoking 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 nonsmoking 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.
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Norgestrel/Ethinyl estradiol Clinical Trials Experience in the drug label.
Postmarketing Experience
There is limited information regarding Norgestrel/Ethinyl estradiol Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Norgestrel/Ethinyl estradiol Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Norgestrel/Ethinyl estradiol in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Norgestrel/Ethinyl estradiol in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Norgestrel/Ethinyl estradiol during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Norgestrel/Ethinyl estradiol in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Norgestrel/Ethinyl estradiol in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Norgestrel/Ethinyl estradiol in geriatric settings.
Gender
There is no FDA guidance on the use of Norgestrel/Ethinyl estradiol with respect to specific gender populations.
Race
There is no FDA guidance on the use of Norgestrel/Ethinyl estradiol with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Norgestrel/Ethinyl estradiol in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Norgestrel/Ethinyl estradiol in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Norgestrel/Ethinyl estradiol in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Norgestrel/Ethinyl estradiol in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Norgestrel/Ethinyl estradiol Administration in the drug label.
Monitoring
There is limited information regarding Norgestrel/Ethinyl estradiol Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Norgestrel/Ethinyl estradiol and IV administrations.
Overdosage
There is limited information regarding Norgestrel/Ethinyl estradiol overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Norgestrel/Ethinyl estradiol Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Norgestrel/Ethinyl estradiol Mechanism of Action in the drug label.
Structure
There is limited information regarding Norgestrel/Ethinyl estradiol Structure in the drug label.
Pharmacodynamics
There is limited information regarding Norgestrel/Ethinyl estradiol Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Norgestrel/Ethinyl estradiol Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Norgestrel/Ethinyl estradiol Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Norgestrel/Ethinyl estradiol Clinical Studies in the drug label.
How Supplied
There is limited information regarding Norgestrel/Ethinyl estradiol How Supplied in the drug label.
Storage
There is limited information regarding Norgestrel/Ethinyl estradiol Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Norgestrel/Ethinyl estradiol Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Cryselle interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Norgestrel/Ethinyl estradiol Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Norgestrel/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.