Loestrin 1 / 20

This section provides information on the proper use of a number of products that contain estrogen and progestin combination (ovarian hormone therapy). It may not be specific to Loestrin 1/20. Please read with care.

Estrogens and progestins usually come with patient information or directions. Read them carefully before taking this medicine.

Take this medicine only as directed by your doctor. Do not take more of it and do not take or use it for a longer time than your doctor ordered. Try to take the medicine at the same time each day to reduce the possibility of side effects and to allow it to work better.

For patients taking estrogens and progestins by mouth:

• Nausea may occur during the first few weeks after you start taking estrogens. This effect usually disappears with continued use. If the nausea is bothersome, it can usually be prevented or reduced by taking each dose with food or immediately after food.

Dosing

The dose medicines in this class will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For 17 beta-estradiol and norgestimate
• For oral dosage forms (tablets):
  • For treating a genital skin condition (vaginal or vulvar atrophy), or vasomotor symptoms of menopause:
    • Adults—Oral, 1 mg estradiol for three days followed by 1 mg of estradiol combined with 0.09 mg of norgestimate for three days. The regimen is repeated continuously without interruption.
  • To prevent loss of bone (osteoporosis):
    • Adults—Oral, 1 mg estradiol for three days followed by 1 mg of estradiol combined with 0.09 mg of norgestimate for three days. The regimen is repeated continuously without interruption.

For ethinyl estradiol and norethindrone
• For oral dosage forms (tablets):
  • For treating vasomotor symptoms of menopause:
    • Adults—Oral, 2.5 mcg (0.025 mg) ethinyl estradiol and 0.5 mg norethindrone once daily.
  • To prevent loss of bone (osteoporosis):
    • Adults—Oral, 2.5 mcg (0.025 mg) ethinyl estradiol and 0.5 mg norethindrone once daily.

For estradiol and norethindrone
• For oral dosage forms (tablets):
  • For treating vasomotor symptoms of menopause or treatment of vaginal or vulvar atrophy:
    • Adults—Oral, 1 mg estradiol and 0.5 mg norethindrone once daily.
  • To prevent loss of bone (osteoporosis):
    • Adults—Oral, 1 mg estradiol and 0.5 mg norethindrone once daily.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Do not keep outdated medicine or medicine no longer needed.

It is very important that your doctor check your progress at regular visits to make sure this medicine does not cause unwanted effects. These visits will usually be every year, but some doctors require them more often.

It is not yet known whether the use of estrogens increases the risk of breast cancer in women. Therefore, it is very important that you regularly check your breasts for any unusual lumps or discharge. Report any problems to your doctor. You should also have a mammogram (x-ray pictures of the breasts) done if your doctor recommends it. Because breast cancer has occurred in men taking estrogens, regular breast self-exams and exams by your doctor for any unusual lumps or discharge should be done.

Tell the doctor in charge that you are taking this medicine before having any laboratory test because some results may be affected.

• It is used to prevent pregnancy.
• It may be given to you for other reasons. Talk with the doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Coughing up blood.
• Shortness of breath.
• Chest pain or pressure.
• Very bad dizziness or passing out.
• Very upset stomach or throwing up.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Swelling, warmth, numbness, change of color, or pain in a leg or arm.
• Very bad headache.
• Low mood (depression).
• Feeling very tired or weak.
• Very bad belly pain.
• Swelling.
• Not able to pass urine or change in how much urine is passed.
• A lump in the breast, breast soreness, or nipple discharge.
• Vaginal itching or discharge.
• Spotting or vaginal bleeding that is very bad or does not go away.
• Bulging eyes.
• Change in eyesight.
• Change in how contact lenses feel in the eyes.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling more or less hungry.
• Dizziness.
• Weight gain.
• Headache.
• Upset stomach or throwing up.
• Stomach cramps.
• Bloating.
• Enlarged breasts.
• Breast soreness.
• Hair loss.
• Lowered interest in sex.
• This medicine may cause dark patches of skin on your face. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.
• Period (menstrual) changes. These include lots of bleeding, spotting, or bleeding between cycles.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Protect from light.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

LOESTRIN 21 and LOESTRIN Fe 28 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.

TABLE I: LOWEST EXPECTED AND TYPICAL FAILURE RATES DURING THE FIRST YEAR OF CONTINUOUS USE OF A METHOD

* The authors' best guess of the percentage of women expected to experience an accidental pregnancy among couples who initiate a method (not necessarily for the first time) and who use it consistently and correctly during the first year if they do not stop for any other reason. † This term represents “typical” couples who initiate use of a method (not necessarily for the first time), who experience an accidental pregnancy during the first year if they do not stop use for any other reason. ‡ N/A--Data not available.
% of Women Experiencing an Unintended Pregnancy in the First Year of Continuous Use
Method	Lowest Expected*	Typical†
(No contraception)	(85)	(85)
Oral contraceptives combined progestin only	0.1 0.5	3 N/A‡ N/A‡
Diaphragm with spermicidal cream or jelly	6	20
Spermicides alone (foam, creams, gels, vaginal suppositories, and vaginal film)	6	26
Vaginal Sponge nulliparous parous	9 20	20 40
Implant	0.05	0.05
Injection: depot medroxyprogesterone acetate	0.3	0.3
IUD progesterone T copper T 380A LNg 20	1.5 0.6 0.1	2 0.8 0.1
Condom without spermicides female male	5 3	21 14
Cervical Cap with spermicidal cream or jelly nulliparous parous	9 26	20 40
Periodic abstinence (all methods)	1 to 9	25
Withdrawal	4	19
Female sterilization	0.5	0.5
Male sterilization	0.10	0.15
Adapted from RA Hatcher et al, Reference 7.

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

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 are strongly advised not to smoke.

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 (10-16). 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 (17). 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.

TABLE II: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE Adapted from P.M. Layde and V. Beral, Reference 18

TABLE II: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE Adapted from P.M. Layde and V. Beral, Reference 18

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 (20-24). Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

b. Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to 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 (9,10,25-30).

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 (31). 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 (15,32). 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 breastfeed.

c. Cerebrovascular Disease

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 (33-35).

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 (36). 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 (36). The attributable risk is also greater in older women (9).

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 (37-39). A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (20-22). 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 (14). 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). 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 (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 (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.

TABLE III: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE

* Deaths are birth related. † Deaths are method related.
Method of control and outcome	15 to 19	20 to 24	25 to 29	30 to 34	35 to 39	40 to 44
No fertility control methods*	7	7.4	9.1	14.8	25.7	28.2
Oral contraceptives non-smoker†	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives smoker†	2.2	3.4	6.6	13.5	51.1	117.2
IUD†	0.8	0.8	1	1	1.4	1.4
Condom*	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/spermicide*	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence*	2.5	1.6	1.6	1.7	2.9	3.6
Adapted from H.W. Ory, Reference 41

3. 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 (42,44,89). 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 (43,45-49,85-88).

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 (51-54). 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.

4. Hepatic Neoplasia

Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States.

Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use (55). Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (56,57).

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (58-60) 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.

5. Ocular Lesions

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

6. Oral Contraceptive Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (61-63). 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.

7. Gallbladder Disease

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens (66,67).

More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (68-70). The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

8. Carbohydrate and Lipid Metabolic Effects

Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users (23). Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (71).

Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (23,72).

However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (73). 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.

9. Elevated Blood Pressure

An increase in blood pressure has been reported in women taking oral contraceptives (74) and this increase is more likely in older oral contraceptive users (75) and with continued use (74). Data from the Royal College of General Practitioners (18) 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 (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).

10. Headache

The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause.

11. Bleeding Irregularities

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

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.

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The patient labeling for oral contraceptive drug products is set forth below:

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Teva Women’s Health, Inc.
Subsidiary of Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454

Rev. A 9/2016