Norgestrel and Ethinyl estradiol

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# Black Box Warning

# Overview
Norgestrel and Ethinyl estradiol is an oral contraceptive agent that is FDA approved for the {{{indicationType}}} of contraception. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include weight changes, abdominal pain, bloating symptom, nausea, vomiting, muscle cramps, headache, mood swings, amenorrhea, break-through bleeding, breast tenderness, discharge from nipple, disorder of menstruation, pain of breast, scanty vaginal bleeding.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Contraception
- Low-Ogestrel(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 I lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception.1 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:
- To achieve maximum contraceptive effectiveness, oral contraceptives must be taken exactly as directed and at intervals not exceeding 24 hours.
- 28-Day Schedule: For a DAY 1 START, count the first day of menstrual flow as Day 1 and the first tablet (white) is then taken on Day 1. For a SUNDAY START when menstrual flow begins on or before Sunday, the first tablet (white) is taken on that day. With either a DAY 1 START or SUNDAY START, 1 tablet (white) is taken each day at the same time for 21 days. Then the peach tablets are taken for 7 days, whether bleeding has stopped or not. After all 28 tablets have been taken, whether bleeding has stopped or not, the same dosage schedule is repeated beginning on the following day.
- INSTRUCTIONS TO PATIENTS
- To achieve maximum contraceptive effectiveness, the oral contraceptive pill must be taken exactly as directed and at intervals not exceeding 24 hours.
- Important: Women should be instructed to use an additional method of protection until after the first 7 days of administration in the initial cycle.
- Due to the normally increased risk of thromboembolism occurring postpartum, women should be instructed not to initiate treatment with oral contraceptives earlier than 4-6 weeks after a full-term delivery. If pregnancy is terminated in the first 12 weeks, the patient should be instructed to start oral contraceptives immediately or within 7 days. If pregnancy is terminated after 12 weeks, the patient should be instructed to start oral contraceptives after 2 weeks.33,77
- If spotting or breakthrough bleeding should occur, the patient should continue the medication according to the schedule. Should spotting or breakthrough bleeding persist, the patient should notify her physician.
- If the patient misses 1 pill, she should be instructed to take it as soon as she remembers and then take the next pill at the regular time. The patient should be advised that missing a pill can cause spotting or light bleeding and that she may be a little sick to her stomach on the days she takes the missed pill with her regularly scheduled pill. If the patient has missed more than one pill, see DETAILED PATIENT LABELING: HOW TO TAKE THE PILL, WHAT TO DO IF YOU MISS PILLS.
- 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 2 consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Norgestrel and Ethinyl estradiol in adult patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Norgestrel and Ethinyl estradiol in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

### Contraception: after menarche
- Dosing information
- use before menarche is not indicated
- Contraception: after menarche, Low-Ogestrel(R), 1 white tablet ORALLY daily for 21 consecutive days, followed by 1 peach tablet daily for 7 consecutive days; during the first cycle, the patient should begin the first Sunday after the onset of menstruation 

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Norgestrel and Ethinyl estradiol in pediatric patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Norgestrel and Ethinyl estradiol in pediatric patients.

# Contraindications
Oral contraceptives should not be used in women who 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, carcinomas or benign liver tumors
- 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, hypercholesterolemia, obesity and diabetes.25
- 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 both 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. Relative risk, the ratio of the incidence of a disease among oral contraceptive users to that among non-users, cannot be assessed directly from case control studies, but the odds ratio obtained is a measure of relative risk. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide not only a measure of relative risk but a measure of attributable risk, which is the difference in the incidence of disease between the oral contraceptive users and non-users. The attributable risk does provide information about the actual occurrence of a disease in the population. (Adapted from ref. 12 and 13 with the authors permission.) For further information, the reader is referred to a text on epidemiological methods.
THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS
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.25, 13 The relative risk of heart attack for current oral contraceptive users has been estimated to be 2 to 6.2, 1419 The risk is very low under the age of 30. However, there is the possibility of a risk of cardiovascular disease even in very young women who take oral contraceptives.
- 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.20
- 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 among women who use oral contraceptives (see Table II).16
- Oral contraceptives may compound the effects of well-known risk factors such as hypertension, diabetes, hyperlipidemias, hypercholesterolemia, age and obesity.3, 13, 21 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.2125 Oral contraceptives have been shown to increase blood pressure among users (see WARNINGS, section 9). 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.
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.12, 13, 2631 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.32 The risk of thromboembolic disease due to oral contraceptives is notrelated to length of use and disappears after pill use is stopped.12
- A 2- to 6-fold increase in relative risk of post-operative 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.83 If feasible, oral contraceptives should be discontinued at least 4 weeks prior to and for 2 weeks after elective surgery and during and following prolonged immobilization. Since the immediate postpartum period also is associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than 4 to 6 weeks after delivery in women who elect not to breast feed.33
Cerebrovascular diseases
- An increase in both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes) has been shown in users of oral contraceptives. 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 non-users for both types of strokes while smoking interacted to increase the risk for hemorrhagic strokes.34
- In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for nor-motensive users to 14 for users with severe hypertension.35 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.35 The attributable risk also is greater in women in their mid-thirties or older and among smokers.13
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.3638 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.2224 A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease.39 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 progestogens used in the contraceptives. The amount of both hormones should be considered in the choice of an oral contraceptive.37
- 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 the lowest estrogen content that produces satisfactory results for the individual.
Persistence of risk of vascular disease
- There are three studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives.17, 34, 40 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 4049 years who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups.17 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.40 There is a significantly increased relative risk of subarachnoid hemorrhage after termination of use of oral contraceptives.34 However, these studies were performed with oral contraceptive formulations containing 50 g or higher of estrogen.
ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE
- One study gathered data from a variety of sources which have estimated the mortality rates associated with different methods of contraception at different ages (see Table III ).41 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 1970sbut not reported in the U.S. until 1983.16,41 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,78, 79 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.80
CARCINOMA OF THE BREAST AND REPRODUCTIVE ORGANS
- Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. The overwhelming evidence in the literature suggests that use of oral contraceptives is not associated with an increase in the risk of developing breast cancer, regardless of the age and parity of first use or with most of the marketed brands and doses.4244 The Cancer and Steroid Hormone (CASH) study also showed no latent effect on the risk of breast cancer for at least a decade following long-term use.43 A few studies have shown a slightly increased relative risk of developing breast cancer,4447 although the methodology of these studies, which included differences in examination of users and non-users and differences in age at start of use, has been questioned.4749 Some studies have reported an increased relative risk of developing breast cancer, particularly at a younger age. This increased relative risk appears to be related to duration of use.81, 82
- 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.5053 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 or 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 per 100,000 for users, a risk that increases after 4 or more years of use.54 Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.5556
- Studies in the United States and Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users.5759 However, these cancers are extremely rare in the United States and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than 1 per 1,000,000 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 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.6062 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.60, 61, 63, 64
- 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 2 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 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.6566 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.67 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.68
CARBOHYDRATE AND LIPID METABOLIC EFFECTS
- Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users.25 Oral contraceptives containing greater than 75 g of estrogen cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance.70 Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.25,71 However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.69 Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.
- Some women may develop persistent hypertriglyceridemia while on the pill.72 As discussed earlier (see WARNINGS, sections 1a. and 1d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.23
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.73,84 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.7375
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 3 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 pre-existent.

### PRECAUTIONS
GENERAL
- 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 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.
LIVER FUNCTION
- If jaundice develops in any woman receiving oral contraceptives 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.
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, and possibly with griseofulvin, ampicillin, and tetracyclines.76
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 steroid 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.
- 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.

# 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, carcinomas 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 Norgestrel and Ethinyl estradiol Postmarketing Experience in the drug label.

# Drug Interactions
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, and possibly with griseofulvin, ampicillin, and tetracyclines.76

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): X
- Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Norgestrel and Ethinyl estradiol in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Norgestrel 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 Low-Ogestrel 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 Norgestrel and Ethinyl estradiol in geriatric settings.

### Gender
There is no FDA guidance on the use of Norgestrel and Ethinyl estradiol with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Norgestrel and Ethinyl estradiol with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Norgestrel and Ethinyl estradiol in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Norgestrel and Ethinyl estradiol in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Norgestrel and Ethinyl estradiol in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Norgestrel and Ethinyl estradiol in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- To achieve maximum contraceptive effectiveness, oral contraceptives must be taken exactly as directed and at intervals not exceeding 24 hours.
- 28-Day Schedule: For a DAY 1 START, count the first day of menstrual flow as Day 1 and the first tablet (white) is then taken on Day 1. For a SUNDAY START when menstrual flow begins on or before Sunday, the first tablet (white) is taken on that day. With either a DAY 1 START or SUNDAY START, 1 tablet (white) is taken each day at the same time for 21 days. Then the peach tablets are taken for 7 days, whether bleeding has stopped or not. After all 28 tablets have been taken, whether bleeding has stopped or not, the same dosage schedule is repeated beginning on the following day.
INSTRUCTIONS TO PATIENTS
- To achieve maximum contraceptive effectiveness, the oral contraceptive pill must be taken exactly as directed and at intervals not exceeding 24 hours.
- Important: Women should be instructed to use an additional method of protection until after the first 7 days of administration in the initial cycle.
- Due to the normally increased risk of thromboembolism occurring postpartum, women should be instructed not to initiate treatment with oral contraceptives earlier than 4-6 weeks after a full-term delivery. If pregnancy is terminated in the first 12 weeks, the patient should be instructed to start oral contraceptives immediately or within 7 days. If pregnancy is terminated after 12 weeks, the patient should be instructed to start oral contraceptives after 2 weeks.33,77
- If spotting or breakthrough bleeding should occur, the patient should continue the medication according to the schedule. Should spotting or breakthrough bleeding persist, the patient should notify her physician.
- If the patient misses 1 pill, she should be instructed to take it as soon as she remembers and then take the next pill at the regular time. The patient should be advised that missing a pill can cause spotting or light bleeding and that she may be a little sick to her stomach on the days she takes the missed pill with her regularly scheduled pill. If the patient has missed more than one pill, see DETAILED PATIENT LABELING: HOW TO TAKE THE PILL, WHAT TO DO IF YOU MISS PILLS.
- 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 2 consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

### Monitoring
- 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.
- 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 Norgestrel 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.
NON-CONTRACEPTIVE 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.611
- 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

# Pharmacology
There is limited information regarding Norgestrel and Ethinyl estradiol Pharmacology in the drug label.

## Mechanism of Action
- Combination oral contraceptives act by suppression of gonadotrophins. 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 may reduce the likelihood of implantation).

## Structure
- Low-Ogestrel  Tablets (norgestrel and ethinyl estradiol tablets USP, 0.3 mg/0.03 mg) provide an oral contraceptive regimen consisting of 21 white tablets followed by 7 peach tablets.
- Each white tablet, for oral administration contains 0.3 mg of norgestrel and 0.03 mg ethinyl estradiol and the following inactive ingredients: croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, and povidone.
- Each inactive peach tablet, for oral administration, in the 28 day regimen contains the following inactive ingredients: anhydrous lactose, FD&C Yellow No. 6 Lake, lactose monohydrate, magnesium stearate, and microcrystalline cellulose.
- Norgestrel is a totally synthetic progestogen, insoluble in water, freely soluble in chloroform, sparingly soluble in alcohol with the chemical name ()-13-Ethyl-17-hydroxy-18,19-dinor-17-pregn-4-en-20-yn-3-one. Ethinyl estradiol is an estrogen, insoluble in water, soluble in alcohol, in chloroform, in ether, in vegetable oils, and in solutions of fixed alkali hydroxides with the chemical name 19-nor-17-pregna-1,3,5(10)-trien-20-yne-3,17-diol. Their structural formulae follow:
- Therapeutic class: Oral contraceptive.

## Pharmacodynamics
There is limited information regarding Norgestrel and Ethinyl estradiol Pharmacodynamics in the drug label.

## Pharmacokinetics
There is limited information regarding Norgestrel and Ethinyl estradiol Pharmacokinetics in the drug label.

## Nonclinical Toxicology
There is limited information regarding Norgestrel and Ethinyl estradiol Nonclinical Toxicology in the drug label.

# Clinical Studies
There is limited information regarding Norgestrel and Ethinyl estradiol Clinical Studies in the drug label.

# How Supplied
- Low-Ogestrel Tablets (norgestrel and ethinyl estradiol tablets USP, 0.3 mg/0.03 mg): Each white tablet is unscored, round in shape, with 847 debossed on one side and WATSON on the other side, and contains 0.3 mg norgestrel and 0.03 mg ethinyl estradiol. Low-Ogestrel is packaged in cartons of three and six tablet dispensers. Each tablet dispenser contains 21 white (active) tablets and 7 peach (inert) tablets. Inert tablets are unscored, round in shape with WATSON debossed on one side and P1 on the other side.

## Storage
- Store at controlled room temperature 15oC to 25oC (59oF to 77oF).
- Keep this and all medications out of the reach of children.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- To achieve maximum contraceptive effectiveness, the oral contraceptive pill must be taken exactly as directed and at intervals not exceeding 24 hours.
- Important: Women should be instructed to use an additional method of protection until after the first 7 days of administration in the initial cycle.
- Due to the normally increased risk of thromboembolism occurring postpartum, women should be instructed not to initiate treatment with oral contraceptives earlier than 4-6 weeks after a full-term delivery. If pregnancy is terminated in the first 12 weeks, the patient should be instructed to start oral contraceptives immediately or within 7 days. If pregnancy is terminated after 12 weeks, the patient should be instructed to start oral contraceptives after 2 weeks.33,77
- If spotting or breakthrough bleeding should occur, the patient should continue the medication according to the schedule. Should spotting or breakthrough bleeding persist, the patient should notify her physician.
- If the patient misses 1 pill, she should be instructed to take it as soon as she remembers and then take the next pill at the regular time. The patient should be advised that missing a pill can cause spotting or light bleeding and that she may be a little sick to her stomach on the days she takes the missed pill with her regularly scheduled pill. If the patient has missed more than one pill, see DETAILED PATIENT LABELING: HOW TO TAKE THE PILL, WHAT TO DO IF YOU MISS PILLS.
- 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 2 consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

# Precautions with Alcohol
- Alcohol-Norgestrel and Ethinyl estradiol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
Ovral,
Lo/Ovral,
Ogestrel,
Low-Ogestrel,
Cryselle.

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

# Drug Shortage Status

# Price