Balziva

Oral contraceptives 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 1 lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

TABLE 1: LOWEST EXPECTED AND TYPICAL FAILURE RATES DURING THE FIRST YEAR OF CONTINUOUS USE OF A METHOD % of Women Experiencing an Accidental Pregnancy in the First Year of Continuous Use

* 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 reason other than pregnancy. † 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 reason other than pregnancy. ‡ Combined typical rate for both combined and progestin only. § Combined typical rate for both medicated and nonmedicated IUD.
Method	Lowest Expected*	Typical†
(No contraception)	(85)	(85)
Oral contraceptives
combined	0.1	3‡
progestin only	0.5	3‡
Diaphragm with spermicidal cream or jelly	6	18
Spermicides alone (foam, creams, jellies and vaginal suppositories)	3	21
Vaginal sponge
nulliparous	6	18
multiparous	9	28
IUD	0.8 to 2	3§
Condom without spermicides	2	12
Periodic abstinence (all methods)	1 to 9	20
Injectable progestogen	0.3 to 0.4	0.3 to 0.4
Implants
6 capsules	0.04	0.04
2 rods	0.03	0.03
Female sterilization	0.2	0.4
Male sterilization	0.1	0.15
Reproduced with permission of the Population Council from J. Trussell, et. al: Contraceptive failure in the United States: An update. Studies in Family Planning, 21(1), January-February 1990.

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 • Cerebrovascular 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 • Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see WARNINGS, Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment).

The use of oral contraceptives is associated with increased risk 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*. For further information, the reader is referred to a text on epidemiological methods.

*Adapted from Stadel BB: Oral contraceptives and cardiovascular disease. N Engl J Med, 1981; 305: 612-618, 672-677; with author’s permission.

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

1. Thromboembolic Disorders and Other Vascular Problems

The physician should be alert to the earliest manifestations of thromboembolic thrombotic disorders as discussed below. Should any of these occur or be suspected the drug should be discontinued immediately.

a. Myocardial Infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older, with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Figure 1) among women who use oral contraceptives.

FIGURE 1: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE

Layde PM, Beral V: Further analyses of mortality in oral contraceptive users: Royal College of General Practitioners’ oral contraception study. (Table 5) Lancet 1981;1:541-546.

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 10 in WARNINGS). Such increases in risk factors have been associated with an increased risk of heart disease and the risk increases with the number of risk factors present. 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. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breastfeed.

c. Cerebrovascular Diseases

Oral contraceptives have been shown to increase both the relative and attributable risk 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 non-users, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women.

d. Dose-Related Risk of Vascular Disease from Oral Contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing 0.05 mg or less of estrogen.

e. Persistence of Risk

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 old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least six years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.

2. Estimates of Mortality from 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 2).

TABLE 2: 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.
	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
Ory HW: Mortality associated with fertility and fertility control: 1983. Fam Plann Perspect 1983; 15:50-56.

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 risk. 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. 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, Jick H, 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 risk may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.

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. The overwhelming evidence in the literature suggests that use of oral contraceptives is not associated with an increase in the risk of developing breast cancer, regardless of the age and parity of first use or with most of the marketed brands and doses. The Cancer and Steroid Hormone (CASH) study also showed no latent effect on the risk of breast cancer for at least a decade following long-term use. A few studies have shown a slightly increased relative risk of developing breast cancer, although the methodology of these studies, which included differences in examination of users and nonusers and differences in age at start of use, has been questioned.

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.

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 cancer 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 their occurrence 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. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma 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. Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications such as COCs. Discontinue Balziva prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS). Balziva can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen.

6. 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.

7. 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. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, 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.

8. Gallbladder Disease

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.

The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

9. Carbohydrate and Lipid Metabolic Effects

Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.

However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. 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.

10. Elevated Blood Pressure

An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens.

Women with a history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users.

11. 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.

12. Bleeding Irregularities

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

Women with a history of oligomenorrhea or secondary amenorrhea or young women without regular cycles prior to taking oral contraceptives may again have irregular bleeding or amenorrhea after discontinuation of oral contraceptives.

See patient labeling printed below.

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section):

• Thrombophlebitis • Arterial thromboembolism • Pulmonary embolism • Myocardial infarction • Cerebral hemorrhage • Cerebral thrombosis • Hypertension • Gallbladder disease • Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed:

• Mesenteric thrombosis • Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:

• Nausea • Vomiting • Gastrointestinal symptoms (such as abdominal cramps and bloating) • Breakthrough bleeding • Spotting • Change in menstrual flow • Amenorrhea • Temporary infertility after discontinuation of treatment • Edema • Melasma which may persist • Breast changes: tenderness, enlargement, and secretion • Change in weight (increase or decrease) • Change in cervical ectropion and secretion • Possible diminution in lactation when given immediately postpartum • Cholestatic jaundice • Migraine • Rash (allergic) • Mental depression • Reduced tolerance to carbohydrates • Vaginal candidiasis • Change in corneal curvature (steepening) • Intolerance to contact lenses

The following adverse reactions have been reported in users of oral contraceptives, and the association has been neither confirmed nor refuted:

• Premenstrual syndrome • Cataracts • Changes in appetite • Cystitis-like syndrome • Headache • Nervousness • Dizziness • Hirsutism • Loss of scalp hair • Erythema multiforme • Erythema nodosum • Hemorrhagic eruption • Vaginitis • Porphyria • Impaired renal function • Hemolytic uremic syndrome • Budd-Chiari syndrome • Acne • Changes in libido • Colitis

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

Other dosage forms:

• oral tablet, oral tablet chewable

Along with its needed effects, ethinyl estradiol / norethindrone may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking ethinyl estradiol / norethindrone:

Incidence not known

• Abdominal or stomach pain
• absent, missed, or irregular menstrual periods
• anxiety
• change in vision
• changes in skin color
• chest pain or discomfort
• chills
• clay-colored stools
• constipation
• cough
• dark urine
• diarrhea
• dizziness or lightheadedness
• fainting
• fast heartbeat
• fever
• headache
• hives or welts
• itching skin
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• medium to heavy, irregular vaginal bleeding between regular monthly periods, which may require the use of a pad or a tampon
• nausea and vomiting
• pain or discomfort in the arms, jaw, back, or neck
• pain, tenderness, or swelling of the foot or leg
• pains in the chest, groin, or legs, especially in the calves of the legs
• pounding in the ears
• rash
• redness of the skin
• severe headaches of sudden onset
• slow or fast heartbeat
• sudden loss of coordination or slurred speech
• sudden onset of shortness of breath for no apparent reason
• sudden shortness of breath or troubled breathing
• sweating
• unusual tiredness or weakness
• vomiting of blood

Some side effects of ethinyl estradiol / norethindrone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Incidence not known

• Abdominal or stomach cramps
• bloating
• blotchy spots on the exposed skin
• breast enlargement or tenderness
• discouragement
• feeling sad or empty
• irritability
• itching of the vagina or outside genitals
• loss of interest or pleasure
• pain during sexual intercourse
• thick, white curd-like vaginal discharge without odor or with mild odor
• tiredness
• trouble concentrating
• trouble sleeping
• trouble wearing contact lenses