Zeosa

Zeosa™ norethindrone and ethinyl estradiol tablets USP (chewable) and ferrous fumarate tablets USP (chewable) provides a regimen for oral contraception derived from 21 light yellow tablets composed of norethindrone and ethinyl estradiol followed by 7 brown ferrous fumarate (placebo) tablets. The chemical name for norethindrone is 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one and for ethinyl estradiol the chemical name is 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. The structural formulas are:

NORETHINDRONEETHINYL ESTRADIOL
C20H26O2 C20H24O2
Molecular Weight: 298.42 Molecular Weight: 296.40

The active light yellow norethindrone and ethinyl estradiol tablets contain 0.4 mg norethindrone USP and 0.035 mg ethinyl estradiol USP and the following inactive ingredients: anhydrous lactose, ferric oxide, magnesium stearate, natural spearmint flavor (gum acacia and maltodextrin), pregelatinized starch and sucralose powder.

The inert brown ferrous fumarate tablets contain confectioner’s sugar, ferrous fumarate USP, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sucralose powder and povidone. The ferrous fumarate tablets do not serve any therapeutic purpose.

Zeosa™ norethindrone and ethinyl estradiol tablets USP (chewable) and ferrous fumarate tablets USP (chewable) are 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 2 lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and implants, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

Table 2: Percentage of women experiencing an unintended pregnancy during the first year of typical use and the first year of perfect use of contraception and the percentage continuing use at the end of the first year. United States.

	% of Women Experiencing an Unintended Pregnancy within the First Year of Use		% of Women Continuing Use at One Year3
Method (1)	Typical Use1 (2)	Perfect Use2 (3)	(4)
Chance4	85	85
Spermicides5	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation Method		3
Sympto-thermal6		2
Post-Ovulation		1
Cap7
Parous Women	40	26	42
Nulliparous Women	20	9	56
Sponge
Parous Women	40	20	42
Nulliparous Women	20	9	56
Diaphragm7	20	6	56
Withdrawal	19	4
Condom8
Female (reality)	21	5	56
Male	14	3	61
Pill	5		71
Progestin only		0.5
Combined		0.1
IUD
Progesterone T	2	1.5	81
Copper T 380A	0.8	0.6	78
LNg 20	0.1	0.1	81
Depo-Provera®	0.3	0.3	70
Norplant® and Norplant® 2	0.05	0.05	88
Female Sterilization	0.5	0.5	100
Male Sterilization	0.15	0.10	100
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces risk of pregnancy by at least 75%.9 Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10 Source: Trussell J, Stewart F, Contraceptive Efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998.

1 Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason

2 Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason

3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year

4 The percentage of women becoming pregnant noted in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% became pregnant in one year. This estimate was lowered slightly (to 85%) to represent the percentage that would become pregnant within one year among women now relying on reversible methods of contraception if they abandon contraception altogether

5 Foams, creams, gels, vaginal suppositories and vaginal film

6 Cervical mucous (ovulation) method supplemented by calendar in the preovulatory and basal body temperature in the postovulatory phases

7 With spermicidal cream or jelly

8 Without spermicides

9 The treatment schedule is one dose within 72 hours after unprotected intercourse and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 2 light orange pills), Lo/Ovral® (1 dose is 4 white pills), Triphasil® or Tri-Levlen® (1 dose is 4 yellow pills)

10 However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced or the baby reaches six months of age

Combination oral contraceptives should not be used in women who currently have the following conditions:

• Thrombophlebitis or thromboembolic disorders • History of deep vein thrombophlebitis or thromboembolic disorders • Cerebrovascular or coronary artery disease (current or history) • Valvular heart disease with thrombogenic complications • Uncontrolled hypertension • Diabetes with vascular involvement • Headaches with focal neurological symptoms, such as aura • Major surgery with prolonged immobilization • Known or suspected carcinoma of the breast or personal history of breast cancer • 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, or active liver disease • Known or suspected pregnancy • Hypersensitivity to any component of this product

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.

NONCONTRACEPTIVE HEALTH BENEFITS

The following noncontraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral-contraceptive formulations containing doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol.

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

To achieve maximum contraceptive effectiveness, Zeosa tablets must be taken exactly as directed and at intervals not exceeding 24 hours. The dosage is one light yellow tablet daily for 21 consecutive days, followed by one brown tablet daily for 7 consecutive days. It is recommended that tablets be taken at the same time each day. The pill may be swallowed whole or chewed and swallowed. If the pill is chewed, the patient should drink a full glass (8 ounces) of liquid immediately after swallowing. During the first cycle of use, the patient is instructed to begin taking tablets on either Day 1 or the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first tablet (light yellow) is taken that day. One light yellow tablet should be taken daily for 21 consecutive days followed by one brown tablet daily for 7 consecutive days. Withdrawal bleeding should usually occur within three days following discontinuation of light yellow tablets and may not have finished before the next pack is started. During the first cycle with a Sunday start, contraceptive reliance should not be placed on norethindrone and ethinyl estradiol tablets, until a light yellow tablet has been taken daily for 7 consecutive days and a nonhormonal back-up method of birth control (such as condoms or spermicides) should be used during those 7 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 on which she began her first course, following the same schedule: 21 days on light yellow tablets7 days on brown tablets. If in any cycle the patient starts tablets later than the proper day, she should protect herself against pregnancy by using a nonhormonal back-up method of birth control until she has taken a light yellow tablet daily for 7 consecutive days.

When the patient is switching from a 21-day regimen of tablets, she should wait 7 days after her last tablet before she starts norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable). She will probably experience withdrawal bleeding during that week. She should be sure that no more than 7 days pass after her previous 21-day regimen. When the patient is switching from a 28-day regimen of tablets, she should start her first pack of norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) on the day after her last tablet. She should not wait any days between packs. The patient may switch any day from a progestin-only pill and should begin norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) the next day. If switching from an implant or injection, the patient should start norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) on the day of implant removal or, if using an injection, the day the next injection would be due.

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 healthcare provider. Although pregnancy is unlikely if norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) are 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. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. Hormonal contraceptives should be discontinued if pregnancy is confirmed.

For additional patient instructions regarding missed pills, see the “WHAT TO DO IF YOU MISS PILLS” section in the DETAILED PATIENT LABELING. Any time the patient misses two or more light yellow tablets, she should also use another method of nonhormonal back-up contraception until she has taken a light yellow tablet daily for seven consecutive days. If the patient misses one or more brown tablets, she is still protected against pregnancy provided she begins taking light yellow tablets again on the proper day. If breakthrough bleeding occurs following missed light yellow tablets, it will usually be transient and of no consequence. The possibility of ovulation increases with each successive day that scheduled light yellow tablets are missed. The risk of pregnancy increases with each active (light yellow) tablet missed.

Norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) may be initiated no earlier than day 28 postpartum in the nonlactating mother due to the increased risk for thromboembolism. 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). The patient should be advised to use a nonhormonal back-up method for the first 7 days of tablet-taking. However, if intercourse has already occurred, the possibility of ovulation and conception prior to initiation of medication should be considered. Norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) may be initiated after a first-trimester abortion; if the patient starts norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) immediately, additional contraceptive measures are not needed.

For additional patient instructions regarding complete dosing instructions, see the “HOW TO TAKE THE PILL” section in the DETAILED PATIENT LABELING.

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

Oral contraceptives, also known as “birth control pills” or “the pill”, are taken to prevent pregnancy, and when taken correctly without missing any pills, have a failure rate of about 1% per year (1 pregnancy per 100 women per year of use). The typical failure rate of pill users is 5% per year (5 pregnancies per 100 women per year of use) when women who miss pills are included.

For the majority of women, oral contraceptives can be taken safely. But for some women oral contraceptive use is associated with certain serious diseases that can be life-threatening or may cause temporary or permanent disability or death. The risks associated with taking oral contraceptives increase significantly if you:

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

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

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 also greater potential health risks associated with pregnancy in older women.

Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels from oral contraceptive use. This risk increases with age and with the amount of smoking (15 or more cigarettes per day has been associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should not smoke.

Most side effects of the pill are not serious. The most common are nausea, vomiting, bleeding or spotting between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting, may decrease or subside within the first three months of use.

The serious side effects of the pill occur very infrequently, especially if you are in good health and do not smoke. However, you should know that the following medical conditions have been associated with or made worse by the pill:

1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris), or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. Women with migraine also may be at increased risk of stroke when taking the pill. 2. Liver tumors, which may rupture and cause severe bleeding. A possible but not definite association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer. 3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped.

The symptoms associated with these serious side effects are discussed in the detailed patient information leaflet given to you with your supply of pills. Notify your healthcare provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, and herbal preparations containing St. John's Wort (hypericum perforatum), may decrease oral contraceptive effectiveness.

Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This very small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the difference is caused by the pill. It may be that women taking the pill are examined more often, so that breast cancer is more likely to be detected. You should have regular breast examinations by a healthcare provider and examine your own breasts monthly. Tell your healthcare provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use hormonal contraceptives because breast cancer is usually a hormone-sensitive tumor.

Some studies have found an increase in the incidence of cancer or precancerous lesions of the cervix in women who use the pill. However, this finding may be related to factors other than the use of the pill.

Taking the combination pill provides some important noncontraceptive health benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus.

Be sure to discuss any medical condition you may have with your healthcare provider. Your healthcare provider will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare provider believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information leaflet gives you further information which you should read and discuss with your healthcare provider.

Dosage and Administration

HOW TO TAKE Zeosa™ NORETHINDRONE AND ETHINYL ESTRADIOL TABLETS USP (CHEWABLE) AND FERROUS FUMARATE TABLETS USP (CHEWABLE)

IMPORTANT POINTS TO REMEMBER

BEFORE YOU START TAKING YOUR PILLS

1. BE SURE TO READ THESE DIRECTIONS:   ● Before you start taking your pills   ● Anytime you are not sure what to do 2. THE PILL MAY BE SWALLOWED WHOLE OR CHEWED AND SWALLOWED. IF THE PILL IS CHEWED, YOU SHOULD DRINK A FULL GLASS (8 OUNCES) OF LIQUID IMMEDIATELY AFTER SWALLOWING. 3. TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 4. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1 to 3 PACKS OF PILLS.
If you have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it does not go away, check with your healthcare provider. 5. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 6. IF YOU HAVE VOMITING (within 3 to 4 hours after you take your pill), you should follow the instructions for WHAT TO DO IF YOU MISS PILLS. IF YOU HAVE DIARRHEA or IF YOU TAKE CERTAIN MEDICINES, including some antibiotics, or the herbal supplement St. John’s Wort, your pills may not work as well. Use a back-up method of birth control (such as condoms or spermicides) until you check with your healthcare provider. 7. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare provider about how to make pill-taking easier or about using another method of birth control. 8. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare provider.

BEFORE YOU START TAKING YOUR PILLS

1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take Zeosa tablets at about the same time every day. 2. LOOK AT YOUR PILL PACK:
The Zeosa pill pack has 21 “active” light yellow pills (with hormones) to take for 3 weeks, followed by 7 “reminder” brown pills (without hormones) to take for 1 week. 3. ALSO FIND:   ● where on the pack to start taking pills,   ● in what order to take the pills (follow the arrows), and   ● the week numbers as shown in the picture below. 4. BE SURE YOU HAVE READY AT ALL TIMES:   ● ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicides) to use as a back-up in case you miss pills.   ● AN EXTRA, FULL PILL PACK.

WHEN TO START THE FIRST PACK OF PILLS

You have 2 choices of which day to start taking your first pack of pills. (See DAY 1 START or SUNDAY START directions below.) Decide with your healthcare provider which is the best day for you. Once you have decided which day you will begin taking your pills, immediately do the following: remove the Combination Brief Summary/Detailed Patient Labeling from inside the pouch and look for the attached day label sheet; peel the label from the sheet which has the start day printed on the left hand side; place the label on the blister card in the designated location. Take your pill daily in the order indicated by the arrows on the blister card. Pick a time of day which will be easy to remember and take your pill at the same time each day.

DAY 1 START

1. Take the first “active” light yellow pill of the first pack during the first 24 hours of your period. 2. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period.

SUNDAY START

1. Take the first “active” light yellow pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or spermicides are good back-up methods of birth control.

WHAT TO DO DURING THE MONTH

1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.
Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea).
Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OF Zeosa tablets:
Start the next pack on the day after your last brown “reminder” pill. Do not wait any days between packs. 3. WHEN YOU SWITCH FROM A DIFFERENT BRAND OF PILLS:
If your previous brand had 21 pills, wait 7 days before starting Zeosa tablets.
If your previous brand had 28 pills, start Zeosa tablets on the day after the last pill.

WHAT TO DO IF YOU MISS PILLS

The pill may not be as effective if you miss light yellow “active” pills, and particularly if you miss the first few or the last few light yellow “active” pills in a pack.

If you MISS 1 light yellow “active” pill

1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex.

If you MISS 2 light yellow “active” pills in a row in WEEK 1 OR WEEK 2 of your pack

1. Take 2 pills on the day you remember and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You COULD BECOME PREGNANT if you have sex during the 7 days after you restart your pills. You MUST use a nonhormonal birth control method (such as condoms or spermicides) as a back-up for those 7 days.

If you MISS 2 light yellow “active” pills in a row in THE 3rd WEEK

1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
If you are a Sunday Starter
Keep taking 1 pill every day until Sunday.
On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare provider because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex during the 7 days after you restart your pills. You MUST use a nonhormonal birth control method (such as condoms or spermicides) as a back-up for those 7 days.

If you MISS 3 OR MORE light yellow “active” pills in a row (during the first 3 weeks)

1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
If you are a Sunday Starter
Keep taking 1 pill every day until Sunday.
On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare provider because you might be pregnant. 3. You COULD BECOME PREGNANT if you have sex on the days when you missed pills or during the first 7 days after restarting your pills. You MUST use a nonhormonal birth control method (such as condoms or spermicides) as a back-up for the first 7 days after you restart your pills.

If you forget any of the 7 brown “reminder” pills in Week 4

1. THROW AWAY the pills you missed. 2. Keep taking 1 pill each day until the pack is empty. 3. You do not need a back-up method of birth control.

FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED

1. Use a BACK-UP METHOD anytime you have sex. 2. KEEP TAKING ONE “ACTIVE” (LIGHT YELLOW) PILL EACH DAY until you can reach your healthcare provider.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088.

DETAILED PATIENT PACKAGE INSERT

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

INTRODUCTION

Any woman who considers using oral contraceptives (the “birth control pill” or “the pill”) should understand the benefits and risks of using this form of birth control.

Although oral contraceptives have important advantages over other methods of contraception, they have certain risks that no other method has, and some of these risks may continue after you have stopped using the oral contraceptive. This leaflet will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use Zeosa tablets properly so that it will be as effective as possible. However, this booklet is not a replacement for a careful discussion between you and your healthcare provider. You should discuss the information provided in this booklet with your healthcare provider, both when you first start taking the pill and during your revisits. You should also follow your healthcare provider’s advice with regard to regular check-ups while you are on Zeosa tablets.

EFFECTIVENESS OF ORAL CONTRACEPTIVES

Oral contraceptives or “birth control pill” or “the pill” are used to prevent pregnancy and are more effective than most other nonsurgical methods of birth control. The chance of becoming pregnant is approximately 1% per year (1 pregnancy per 100 women per year of use) when the pills are used correctly, and no pills are missed. Typical failure rates are 5% per year (5 pregnancies per 100 women per year of use) when women who miss pills are included. The chance of becoming pregnant increases with each missed pill during a menstrual cycle.

In comparison, typical failure rates for other methods of birth control during the first year of use are as follows:

No methods: 85%

Vaginal sponge: 20 to 40%

Cervical cap: 20 to 40%

Spermicides alone: 26%

Periodic abstinence: 25%

Condom (female): 21%

Diaphragm with spermicides: 20%

Withdrawal: 19%

Condom (male): 14%

Female sterilization: 0.5%

IUD: 0.1 to 2%

Injectable progestogen: 0.3%

Male sterilization: 0.15%

Norplant® system: 0.05%

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES

Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels from oral contraceptive use. This risk increases with age and with the amount of smoking (15 or more cigarettes per day has been associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should not smoke.

Some women should not use Zeosa tablets. You should not use Zeosa tablets if you have or have ever had any of the following conditions:

• A history of heart attack or stroke

• A history of blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes

• A history of blood clots in the deep veins of your legs

• Chest pain (angina pectoris)

• Known or suspected breast cancer or cancer of the lining of the uterus, cervix, vagina, or certain hormonally-sensitive cancers

• Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare provider)

• Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill

• Liver tumor (benign or cancerous)

• Known or suspected pregnancy

• Heart valve or heart rhythm disorders that may be associated with formation of blood clots

• Diabetes affecting your circulation

• Uncontrolled high blood pressure

• Active liver disease with abnormal liver function tests

• Headache with neurological symptoms

• Allergy or hypersensitivity to any of the components of the product

• A need for surgery with prolonged bed rest

Tell your healthcare provider if you have any of the above conditions. Your healthcare provider can recommend a safer method of birth control.

OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES

Tell your healthcare provider if you or any family member has ever had:

• Breast nodules, fibrocystic disease of the breast or an abnormal breast x-ray or mammogram

• Diabetes

• Elevated cholesterol or triglycerides

• High blood pressure

• Migraine or other headaches or epilepsy

• Depression

• Gallbladder, liver, heart, or kidney disease

• History of scanty or irregular menstrual periods

Women with any of these conditions should be checked often by their healthcare provider if they choose to use oral contraceptives.

Also, be sure to inform your healthcare provider if you smoke or are on any medications.

RISKS OF TAKING ORAL CONTRACEPTIVES

1. Risk of developing blood clots

Blood clots and blockage of blood vessels are the most serious side effects of taking oral contraceptives and can cause death or serious disability. In particular, a clot in the legs can cause thrombophlebitis, and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. Either of these can cause death or disability. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision.

If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness or injury, or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your healthcare provider about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breastfeeding. If you are breastfeeding, you should wait until you have weaned your child before using the pill (see the section on breastfeedingin GENERALPRECAUTIONS).

The risk of circulatory disease in oral contraceptive users may be higher in users of high-dose pills (containing 50 micrograms or higher of ethinyl estradiol) and may be greater with longer duration of oral contraceptive use. In addition, some of these increased risks may continue for a number of years after stopping oral contraceptives. The risk of abnormal blood clotting increases with age in both users and nonusers of oral contraceptives, but the increased risk from the oral contraceptive appears to be present at all ages. For women aged 20 to 44 it is estimated that about 1 in 2,000 using oral contraceptives will be hospitalized each year because of abnormal clotting. Among nonusers in the same age group, about 1 in 20,000 would be hospitalized each year. For oral contraceptive users in general, it has been estimated that in women between the ages of 15 and 34 the risk of death due to a circulatory disorder is about 1 in 12,000 per year, whereas for nonusers the rate is about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about 1 in 2,500 per year for oral contraceptive users and about 1 in 10,000 per year for nonusers.

2. Heart attacks and strokes

Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or disability.

Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease.

Women with migraine (especially migraine with aura) who take oral contraceptives also may be at higher risk of stroke.

3. Gallbladder disease

Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens.

4. Liver tumors

In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, a possible, but not definite, association has been found with the pill and liver cancers in two studies, in which a few women who developed these very rare cancers were found to have used oral contraceptives for long periods. However, liver cancers in general are extremely rare, and the chance of developing liver cancer from using the pill is thus even rarer.

5. Cancer of the breast and reproductive organs

Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the difference is caused by the pill. It may be that women taking the pill are examined more often, so that breast cancer is more likely to be detected. You should have regular breast examinations by a healthcare provider and examine your own breasts monthly. Tell your healthcare provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram.

Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor.

Some studies have found an increase in the incidence of cancer or precancerous lesions of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such cancers.

6. Lipid metabolism and inflammation of the pancreas

In patients with inherited defects of lipid metabolism, there have been reports of significant elevations of plasma triglycerides during estrogen therapy. This has led to pancreatitis in some cases.

ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY

All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table.

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
	AGE
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 nonsmoker**	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

*Deaths are birth related

**Deaths are method related

In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group.

The suggestion that women over 40 who don't smoke should not take oral contraceptives is based on information from older high-dose pills. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, nonsmoking women over 40 years of age may outweigh the possible risks. Older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestin that is compatible with the individual patient needs.

WARNING SIGNALS

If any of these adverse conditions occur while you are taking oral contraceptives, call your healthcare provider immediately:

• Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung)

• Pain in the calf (indicating a possible clot in the leg)

• Crushing chest pain or heaviness in the chest (indicating a possible heart attack)

• Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke)

• Sudden partial or complete loss of vision (indicating a possible clot in the eye)

• Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your healthcare provider to show you how to examine your breasts)

• Severe pain or tenderness in the stomach area (possibly indicating a ruptured liver tumor)

• Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression)

• Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark-colored urine, or light-colored bowel movements (indicating possible liver problems)

SIDE EFFECTS OF ORAL CONTRACEPTIVES

In addition to the risks and more serious side effects discussed above (see RISKS OF TAKING ORAL CONTRACEPTIVES, ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY and WARNING SIGNALS sections), the following may also occur:

1. Irregular Vaginal Bleeding

Irregular vaginal bleeding or spotting may occur while you are taking norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable). Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your healthcare provider.

2. Contact Lenses

If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your healthcare provider.

3. Fluid Retention

Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your healthcare provider.

4. Melasma

A spotty darkening of the skin is possible, particularly of the face.

5. Other Side Effects

Other side effects may include nausea and vomiting, change in appetite, breast tenderness, headache, nervousness, depression, dizziness, loss of scalp hair, rash, vaginal infections, and allergic reactions.

If any of these side effects bother you, call your healthcare provider.

GENERAL PRECAUTIONS

1. Missed Periods and Use of Oral Contraceptives Before or During Early Pregnancy

There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your healthcare provider. If you have not taken the pills daily as instructed and missed a menstrual period, or if you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare provider immediately to determine whether you are pregnant. Stop taking norethindrone and ethinyl estradiol tablets (chewable) and ferrous fumarate tablets (chewable) if you are pregnant.

There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects but these studies have not been confirmed. Nevertheless, oral contraceptives should not be used during pregnancy. You should check with your healthcare provider about risks to your unborn child of any medication taken during pregnancy.

2. While Breastfeeding

If you are breastfeeding, consult your healthcare provider before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, oral contraceptives may decrease the amount and quality of your milk. If possible, do not use oral contraceptives while breastfeeding. You should use another method of contraception since breastfeeding provides only partial protection from becoming pregnant, and this partial protection decreases significantly as you breastfeed for longer periods of time. You should consider starting oral contraceptives only after you have weaned your child completely.

3. Laboratory Tests

If you are scheduled for any laboratory tests, tell your healthcare provider you are taking birth control pills. Certain blood tests may be affected by birth control pills.

4. Drug Interactions

Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs include rifampin, drugs used for epilepsy such as barbiturates (for example, phenobarbital), carbamazepine (Tegretol® is one brand of this drug), and phenytoin (Dilantin® is one brand of this drug), primidone (Mysoline®), topiramate (Topamax®), phenylbutazone (Butazolidin® is one brand), some drugs used for HIV such as ritonavir (Norvir®), modafinil (Provigil®) and possibly certain antibiotics (such as ampicillin and other penicillins, and tetracyclines), and herbal products containing St. John's wort (hypericum perforatum). You may need to use a nonhormonal method of contraception during any cycle in which you take drugs that can make oral contraceptives less effective. Be sure to tell your healthcare provider if you are taking or start taking any other medications, including nonprescription products or herbal products while taking birth control pills.

You may be at higher risk of a specific type of liver dysfunction if you take troleandomycin (Tao® capsules) and oral contraceptives at the same time.

5. Sexually Transmitted Diseases

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as Chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

HOW TO TAKE Zeosa™norethindrone and ethinyl estradiol tablets USP (CHEWABLE) and ferrous fumarate tablets USP (chewable)

IMPORTANT POINTS TO REMEMBER

BEFORE YOU START TAKING YOUR PILLS

1. BE SURE TO READ THESE DIRECTIONS:

• Before you start taking your pills

• Anytime you are not sure what to do

2. THE PILL MAY BE SWALLOWED WHOLE OR CHEWED AND SWALLOWED. IF THE PILL IS CHEWED, YOU SHOULD DRINK A FULL GLASS (8 OUNCES) OF LIQUID IMMEDIATELY AFTER SWALLOWING.

3. TAKE ONE PILL EVERY DAY AT THE SAME TIME.

If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant.

4. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1 TO 3 PACKS OF PILLS.

If you have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your healthcare provider.

5. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.

On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach.

6. IF YOU HAVE VOMITING (within 3 to 4 hours after you take your pill), you should follow the instructions for WHAT TO DO IF YOU MISS PILLS. IF YOU HAVE DIARRHEA or IF YOU TAKE CERTAIN MEDICINES, including some antibiotics, or the herbal supplement St. John’s Wort, your pills may not work as well. Use a back-up method of birth control (such as condoms or spermicides) until you check with your healthcare provider.

7. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare provider about how to make pill-taking easier or about using another method of birth control.

8. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare provider.

BEFORE YOU START TAKING YOUR PILLS

1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.

It is important to take Zeosa tablets at about the same time every day.

2. LOOK AT YOUR PILL PACK:

The Zeosa pill pack has 21 “active” light yellow pills (with hormones) to take for 3 weeks, followed by 7 “reminder” brown pills (without hormones) to take for 1 week.

3. ALSO FIND:

• where on the pack to start taking pills,

• in what order to take the pills (follow the arrows), and

• the week numbers as shown in the picture below.

4. BE SURE YOU HAVE READY AT ALL TIMES:

• ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicides) to use as a back-up in case you miss pills.

• AN EXTRA, FULL PILL PACK.

WHEN TO START THE FIRST PACK OF PILLS

You have 2 choices of which day to start taking your first pack of pills. (See DAY 1 START OR SUNDAY START directions below.) Decide with your healthcare provider which is the best day for you. Once you have decided which day you will begin taking your pills, immediately do the following: remove the Combination Brief Summary / Detailed Patient Labeling from inside the pouch and look for the attached day label sheet; peel the label from the sheet which has the start day printed on the left hand side; place the label on the blister card in the designated location. Take your pill daily in the order indicated by the arrows on the blister card. Pick a time of day which will be easy to remember and take your pill at the same time each day.

DAY 1 START

1. Take the first “active” light yellow pill of the first pack during the first 24 hours of your period.

2. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period.

SUNDAY START

1. Take the first “active” light yellow pill of the first pack on the Sunday after your period starts , even if you are still bleeding. If your period begins on Sunday, start the pack that same day.

2. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or spermicides are good back-up methods of birth control.

WHAT TO DO DURING THE MONTH

1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY

Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea).

Do not skip pills even if you do not have sex very often.

2. WHEN YOU FINISH A PACK OF Zeosa TABLETS:

Start the next pack on the day after your last brown “reminder” pill. Do not wait any days between packs.

3. WHEN YOU SWITCH FROM A DIFFERENT BRAND OF PILLS:

If your previous brand had 21 pills, wait 7 days before starting Zeosa tablets.

If your previous brand had 28 pills, start taking Zeosa tablets on the day after the last pill.

WHAT TO DO IF YOU MISS PILLS

The pill may not be as effective if you miss light yellow “active” pills, and particularly if you miss the first few or the last few light yellow “active” pills in a pack.

If you MISS 1 light yellow “active” pill

1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day.

2. You do not need to use a back-up birth control method if you have sex.

If you MISS 2 light yellow “active” pills in a row in WEEK 1 OR WEEK 2 of your pack

1. Take 2 pills on the day you remember and 2 pills the next day.

2. Then take 1 pill a day until you finish the pack.

3. You COULD BECOME PREGNANT if you have sex during the 7 days after you restart your pills. You MUST use a nonhormonal birth control method (such as condoms or spermicides) as a back-up for those 7 days.

If you MISS 2 light yellow “active” pills in a row in THE 3rd WEEK

1. If you are a Day 1 Starter :

THROW OUT the rest of the pill pack and start a new pack that same day.

If you are a Sunday Starter

Keep taking 1 pill every day until Sunday.

On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare provider because you might be pregnant.

3. You COULD BECOME PREGNANT if you have sex during the 7 days after you restart your pills. You MUST use a nonhormonal birth control method (such as condoms or spermicides) as a back-up for those 7 days.

If you MISS 3 OR MORE light yellow “active” pills in a row (during the first 3 weeks)

1. If you are a Day 1 Starter :

THROW OUT the rest of the pill pack and start a new pack that same day.

If you are a Sunday Starter

Keep taking 1 pill every day until Sunday.

On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare provider because you might be pregnant.

3. You COULD BECOME PREGNANT if you have sex on the days when you missed pills or during the first 7 days after restarting your pills. You MUST use a nonhormonal birth control method (such as condoms or spermicides) as a back-up for the first 7 days after you restart your pills.

If you forget any of the 7 brown “reminder” pills in Week 4

1. THROW AWAY the pills you missed.

2. Keep taking 1 pill each day until the pack is empty.

3. You do not need a back-up method of birth control.

FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED

1. Use a BACK-UP METHOD anytime you have sex.

2. KEEP TAKING ONE “ACTIVE” (LIGHT YELLOW) PILL EACH DAY until you can reach your healthcare provider.

GENERAL

1. Pregnancy Due to Pill Failure

If taken every day as directed, the incidence of pill failure resulting in pregnancy is approximately 1% per year (one pregnancy per 100 women per year), but more typical failure rates are about 5% per year (5 pregnancies per 100 women per year of use). If pregnancy does occur, the risk to the fetus is minimal.

2. Pregnancy After Stopping the Pill

There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy.

There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill.

3. Overdosage

Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your healthcare provider or pharmacist.

4. Other information

Your healthcare provider will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare provider believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare provider if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your healthcare provider, because this is a time to determine if there are early signs of side effects of oral contraceptive use.

Do not use this drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills.

HEALTH BENEFITS FROM ORAL CONTRACEPTIVES

In addition to preventing pregnancy, use of oral contraceptives may provide certain benefits. They are:

• Menstrual cycles may become more regular

• Blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur

• Pain or other symptoms during menstruation may be encountered less frequently

• Ovarian cysts may occur less frequently

• Ectopic (tubal) pregnancy may occur less frequently

• Noncancerous cysts or lumps in the breast may occur less frequently

• Acute pelvic inflammatory disease may occur less frequently

• Oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus

If you want more information about birth control pills, ask your healthcare provider or pharmacist. They have a more technical leaflet called the Professional Labeling, which you may wish to read.

Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA 1088.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. B 1/2011

Applies to ethinyl estradiol / norethindrone: oral capsule, oral tablet, oral tablet chewable

General

A number of studies have suggested that use of oral contraceptives decreases the risk of ovarian cancer. Specifically, the risk of epithelial ovarian cancers is decreased by 40%. The protection against ovarian cancer may last for 10 to 15 years after discontinuation of oral contraceptives. After long term use (12 years), the risk of ovarian cancer is decreased by as much as 80%.

The risk of endometrial cancer is decreased by approximately 50%. Protection may last for 15 years after discontinuation and may be greatest for nulliparous women who may be at higher risk for endometrial carcinoma than other women.

The incidence of hospitalization for pelvic inflammatory disease is approximately 50% lower in women taking oral contraceptives. The reason for the decrease in the frequency (or severity) of pelvic inflammatory disease in women taking oral contraceptives has not been fully elucidated.

Some recent studies have suggested that the decrease in frequency of functional ovarian cysts reported with some older formulations may not occur in women taking newer low dose formulations.

One recent study (The Nurses' Health Study) has suggested that long term use of oral contraceptives is safe and does not adversely affect long term risk for mortality.[Ref]

Women taking oral contraceptive combinations may have experienced several non-contraceptive health benefits. These benefits include protection against two malignant neoplasms (endometrial carcinoma and ovarian cancer). In addition, use of oral contraceptive combinations has reportedly decreased the frequency of benign breast tumors, decreased the risk of ovarian cysts, decreased the risk of ectopic pregnancy, increased menstrual regularity, decreased the incidence of iron deficiency anemia, decreased the incidence of dysmenorrhea, and decreased the incidence of pelvic inflammatory disease.[Ref]

Gastrointestinal

Gastrointestinal side effects have included nausea, which occurred in approximately 10% of treated women and was more frequent during the first cycles of therapy. Some early reports suggested an association between oral contraceptive use and gallbladder disease.[Ref]

Cases of oral contraceptive-induced esophageal ulceration and geographic tongue have been reported rarely.

More recent studies have suggested that the risk of gallbladder disease is minimal.[Ref]

Oncologic

Oncologic side effects have included reports of increased risk of invasive breast cancer. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease, stroke, and pulmonary embolism. A number of studies have examined a possible relationship between the use of oral contraceptives and the development of breast cancer. Many of the studies have reported conflicting results. A committee of the World Health Organization evaluated these studies and the risks of breast cancer and concluded that: "Numerous studies have found no overall association between oral contraceptive use and risk of breast cancer." In addition, the same committee also examined a possible relationship between oral contraceptive use and neoplasms of the uterine cervix and concluded that: "There are insufficient data to draw any firm conclusions regarding the effects of combined oral contraceptives on the risk of cervical adenocarcinoma."[Ref]

The World Health Organization committee also noted that some studies "have found a weak association between long-term use of oral contraceptives and breast cancer diagnosed before the age of 36, and perhaps up to the age 45....It is unclear whether this observed association is attributable to bias, the development of new cases of cancer, or accelerated growth of existing cancers."

The World Health Organization committee further concluded that there is no increased risk of breast cancer in women over the age of 45 who have previously taken oral contraceptives. In addition, studies suggest that use of oral contraceptives does not place specific groups of women (like those with a family history of breast cancer) at higher or lower risk, and variations in the hormonal content of oral contraceptives do not influence the risk of breast cancer.

In general, studies evaluating the potential risk of cervical cancer in patients taking oral contraceptives have been complicated by the large number of confounding factors which make investigations into the epidemiology of this neoplasm difficult. Some studies have suggested that women taking oral contraceptives are at increased risk of dysplasia, epidermoid carcinoma, and adenocarcinoma of the cervix. However, other studies have not found such an association.[Ref]

Cardiovascular

Detailed information concerning the effects of oral contraceptive therapy on lipid metabolism is available in the Endocrine paragraph of this side effect monograph.

Some early investigations of women taking high dose estrogen combinations (50 mcg or more of ethinyl estradiol or equivalent daily) suggested that such women may be at increased risk of cardiovascular complications (myocardial infarction, stroke, and vascular thrombosis, including venous thromboembolism). However, more recent large investigations of women taking low dose estrogen combinations have suggested that oral contraceptive use is not associated with an increased risk of serious cardiovascular complications in healthy non smoking women up to the age of 45. (For women aged 35 to 44 who smoke or who have preexisting systemic diseases that may affect the cardiovascular system, use of oral contraceptives is not recommended.)

However, some investigators have suggested that even the new low dose products may result in adverse effects on lipid metabolism and should prompt careful review of a woman's cardiovascular risk factors before a decision to use oral contraceptive combinations is made.

The frequency of both subarachnoid hemorrhage and thrombotic stroke has been reported by some investigators to be higher in women taking oral contraceptive hormones. However, other investigators have suggested that the risk of these effects for women using newer low dose formulations are very small for young women without underlying cardiovascular disease or other risk factors.[Ref]

Cardiovascular side effects have included reports of increased risk of coronary heart disease, stroke, and pulmonary embolism. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease, stroke, and pulmonary embolism. Earlier studies had suggested that unopposed estrogen therapy may decrease the risk of coronary heart disease by as much as 35% and that combination therapy with a progestin may also decrease coronary risk. Cardiovascular side effects of the estrogen component of this combination have also included reports of hypertension. However, significant blood pressure increases generally occur only in women receiving high-dose estrogen products (50 mcg or more of ethinyl estradiol or equivalent daily). Estrogens have also been associated with edema. In addition, exogenous estrogens may exert cardioprotective effects by causing favorable changes in lipid profiles. These beneficial effects, however, may be partially or completely offset by alterations in lipid profiles induced by exogenous progestins.[Ref]

Endocrine

Endocrine side effects have included reports of complex alterations in plasma lipid profiles and carbohydrate metabolism. In addition, oral contraceptive use has been reported to cause conception delay.[Ref]

All the progestins which occur in commercially available oral contraceptive combinations have adverse effects on lipid profiles. Specifically, these progestins exert antiestrogen and androgen effects and decrease HDL (and HDL2) cholesterol levels and increase LDL cholesterol levels. However, the estrogens in oral contraceptive combinations exert opposing effects. Consequently, alterations in lipid profiles are related to the relative amount and potency of the specific estrogen and progestin in a given product. (Norethindrone exerts a moderate androgen effect and weak progestin and antiestrogen effects.)

A number of investigations have suggested that oral contraceptive combinations may decrease glucose tolerance. However, some recent studies with low dose preparations have suggested that decreases in glucose tolerance due to oral contraceptive combinations are generally minimal.

Despite the potentially adverse effects of oral contraceptives on lipid levels and glucose tolerance, some investigators have suggested that young diabetic women without existing vascular disease or severe lipidemias may be candidates for low dose oral contraceptive combinations provided that they receive close monitoring for adverse metabolic effects.[Ref]

Hepatic

Hepatic side effects have included focal nodular hyperplasia, intrahepatic cholestasis, liver cell adenomas, hepatic granulomas, hepatic hemangiomas and well-differentiated hepatocellular carcinomas, which have been reported rarely in association with estrogen therapy and therapy with oral contraceptive combinations.[Ref]

The rate of death due to hepatocellular carcinoma in the United States has not changed during the last 25 years (a time during which use of oral contraceptive hormones has increased dramatically).

A committee of the World Health Organization has reported that in developing countries where hepatitis B virus infection and hepatocellular carcinoma are common, "short term use of oral contraceptives does not appear to be associated with an increased risk. Data on the effects of long term use are scarce."

A recent Italian case-control study of women with hepatocellular carcinoma has suggested that the relative risk of hepatocellular carcinoma is 2.2 for oral contraceptive users compared to women who never used oral contraceptives.

A similar American case-control study from 1989 also reported a strong association between oral contraceptive use and hepatocellular carcinoma but concluded that: "If this observed association is causal, the actual number of cases of liver cancer in the United States attributable to oral contraceptive use is small. Therefore, these findings do not have public health importance in the United States and other Western nations."[Ref]

Hematologic

Cases of venous thrombosis, pulmonary embolism (sometimes fatal), and arterial thrombosis have been reported rarely.

Previous thrombotic disease is considered a contraindication to use of oral contraceptive combinations.[Ref]

Hematologic side effects have included the risk of thromboembolism that is associated with the use of exogenous estrogens. However, because the dose of exogenous estrogens is low in most commercially available preparations, the risk of thromboembolism is minimal for most women (except women who are over age 35 and smoke and women with a history of previous thrombotic diseases).[Ref]

Genitourinary

Genitourinary side effects have commonly included breakthrough bleeding and spotting, especially during the first several cycles of oral contraceptive use. Non-hormonal causes of such bleeding should be excluded. Additional side effects reported with estrogen and/or progestin therapy include changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, increase in size of uterine leiomyomata, vaginal candidiasis, change in amount of cervical secretion, change in cervical ectropion, ovarian cancer, endometrial hyperplasia, endometrial cancer and vaginitis.[Ref]

Some women experience oligomenorrhea and amenorrhea following termination or oral contraceptive use.[Ref]

Psychiatric

Psychiatric side effects have included depression and precipitation of panic disorder.[Ref]

Immunologic

Immunologic side effects have included rare cases of oral contraceptive-induced systemic lupus erythematosus.[Ref]

Nervous system

Nervous system side effects have included chorea, which has been reported once in association with oral contraceptives.[Ref]

Ocular

Ocular side effects have included rare cases of retinal thrombosis. In addition, the manufacturers of oral contraceptive products report that some patients develop changes in contact lens tolerance.[Ref]

Respiratory

Respiratory side effects have included reports of increased risk of pulmonary embolism. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease, stroke, and pulmonary embolism.[Ref]

A case of fatal pulmonary venooclusive disease has been associated with oral contraceptive therapy.[Ref]

Some side effects of Zeosa may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.