Ovcon 35 and Ovcon 50
(Norethindrone and Ethinyl Estradiol Tablets, USP)

 21- and 28- DAY REGIMENS

Patients should be counseled that this product does not protect against HIV-infection (AIDS) and other sexually transmitted diseases.

21-Day OVCON^® 35 provides a regimen for oral contraception derived from 21 tablets composed of norethindrone and ethinyl estradiol. 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.

28-Day OVCON^® 35 and OVCON^® 50 (norethindrone and ethinyl estradiol tablets, USP) provide a continuous regimen for oral contraception derived from 21 tablets composed of norethindrone and ethinyl estradiol to be followed by 7 green tablets of inert ingredients. The structural formulas are:

The active OVCON 35 tablets contain 0.4 mg norethindrone and 0.035 mg ethinyl estradiol. The active OVCON 50 tablets contain 1 mg norethindrone and 0.05 mg ethinyl estradiol.

The green tablets contain inert ingredients.

OVCON 35, 21-Day contains the following inactive ingredients: dibasic calcium phosphate, FD&C Yellow No. 6 (aluminum lake), lactose, magnesium stearate, povidone, and sodium starch glycolate.

OVCON 35, 28-Day contains the following inactive ingredients: dibasic calcium phosphate, D&C Yellow No. 10 (aluminum lake), FD&C Blue No. 1 (aluminum lake), FD&C Yellow No. 6 (aluminum lake), lactose, magnesium stearate, povidone, and sodium starch glycolate, starch (corn), and talc.

OVCON 50, 28-Day contains the following inactive ingredients: dibasic calcium phosphate, D&C Yellow No. 10 (aluminum lake), FD&C Blue No. 1 (aluminum lake), FD&C Yellow No. 6 (aluminum lake), lactose, magnesium stearate, povidone, sodium starch glycolate, starch (corn), and talc.

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception. Oral contraceptive products such as OVCON 50, 28-Day, which contain 50 mcg of estrogen, should not be used unless medically indicated.

Oral contraceptives are highly effective. Table 1 uls 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.

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

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.

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).

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 1970s – 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 uled 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.

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.

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.

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.

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.

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.

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 WARNINGS1.a. Myocardial Infarction and 1.d. Dose-related risk of vascular disease from oral contraceptives.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

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.

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.

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.

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.

If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.

Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related.

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. A similar association, though less marked, has been suggested with barbiturates, phenylbutazone, phenytoin sodium, and possibly with griseofulvin, ampicillin, and tetracyclines.

Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:

• Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
• Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T₄ by column or by radioimmunoassay. Free T₃ resin uptake is decreased, reflecting the elevated TBG, free T₄ concentration is unaltered.
• Other binding proteins may be elevated in serum.
• Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.
• Triglycerides may be increased.
• Glucose tolerance may be decreased.
• Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

See WARNINGS section.

Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

Although a cause-and-effect relationship has not been clearly established, several cases of oral contraceptive failure have been reported in association with vomiting and/or diarrhea. If significant gastrointestinal disturbance occurs in any woman receiving contraceptive steroids, the use of a back-up method of contraception for the remainder of that cycle is recommended.

Safety and efficacy of OVCON^® 35 (norethindrone and ethinyl estradiol tablets, USP) and OVCON^® 50 (norethindrone and ethinyl estradiol tablets, USP) have been established in women of reproductive age. Safety and efficacy are expected to be the same in postpubertal adolescents under the age of 16 years and in users ages 16 years and older. Use of this product before menarche is not indicated.

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

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.

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

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

The following is a summary of the instructions given to the patient in the “HOW TO TAKE THE PILL” section of the DETAILED PATIENT PACKAGE INSERT.

The patient is given instructions in five (5) categories.

• IMPORTANT POINTS TO REMEMBER: The patient is told (a) that she should take one pill every day at the same time, (b) many women have spotting or light bleeding or gastric distress during the first one to three cycles, (c) missing pills can also cause spotting or light bleeding, (d) she should use a back-up method for contraception if she has vomiting or diarrhea or takes some concomitant medications, and/or if she has trouble remembering the pill, (e) if she has any other questions, she should consult her physician.
• BEFORE SHE STARTS TAKING HER PILLS : She should decide what time of day she wishes to take the pill, check whether her pill pack has 21 or 28 pills, and note the order in which she should take the pills (diagrammatic drawings of the pill pack are included in the patient insert).
• WHEN SHE SHOULD START THE FIRST PACK: The Day-One start is uled as the first choice and the Sunday start (the Sunday after her period starts) is given as the second choice. If she uses the Sunday start she should use a back-up method in the first cycle if she has intercourse before she has taken seven pills.
• WHAT TO DO DURING THE CYCLE: The patient is advised to take one pill at the same time every day until the pack is empty. If she is on a 21-day regimen, she should wait seven days to start the next pack. If she is on the 28-day regimen, she should start the next pack the day after the last inactive tablet and not wait any days between packs.
• WHAT TO DO IF SHE MISSES A PILL OR PILLS: The patient is given instructions about what she should do if she misses one, two or more than two pills at varying times in her cycle for both the Day-One and the Sunday start. The patient is warned that she may become pregnant if she has unprotected intercourse in the seven days after missing pills. To avoid this, she must use another birth control method such as condom, foam, or sponge in these seven days.

OVCON^® 35 (norethindrone and ethinyl estradiol tablets, USP) is available in 21- and 28-day regimens. Each package contains 21 round, peach tablets of 0.4 mg norethindrone and 0.035 mg ethinyl estradiol, imprinted with MJ on one side and 583 on the other. Each capsule shaped, green tablet in the 28-day regimen contains inert ingredients and is imprinted with MJ on one side and 850 on the other.

OVCON 35, 21-Day

N 0430-0583-11          Carton of 6 compacts

OVCON 35, 28-Day

N 0430-0582-14          Carton of 6 compacts

OVCON^® 50 (norethindrone and ethinyl estradiol tablets, USP) is available in 28-day regimens. Each package contains 21 round, yellow tablets of 1.0 mg norethindrone and 0.05 mg ethinyl estradiol, imprinted with MJ on one side and 584 on the other. Each capsule shaped, green tablet in the 28-day regimen contains inert ingredients and is imprinted with MJ on one side and 850 on the other.

OVCON 50, 28-Day

N 0430-0585-14          Carton of 6 compacts

Store below 30º C (86º F).

References are available upon request.

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

You should not use OVCON 50 (norethindrone and ethinyl estradiol tablets, USP), 28-Day, which contains higher doses of estrogen than other oral contraceptives, unless specifically recommended by your healthcare provider.

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 the 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 booklet 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 the pill 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 health care professional. You should discuss the information provided in this booklet with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare professional’s advice with regard to regular check-ups while you are on the pill.

EFFECTIVENESS OF ORAL CONTRACEPTIVES

Oral contraceptives or “birth control pills” or “the pill” are used to prevent pregnancy and are more effective than other nonsurgical methods of birth control. The chance of becoming pregnant is less than 1% (1 pregnancy per 100 women per year of use) when the pills are used correctly and no pills are missed. Typical failure rates are actually 3% per year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle.

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

IUD: 3%

Diaphragm with spermicides: 18%

Spermicides alone: 21%

Vaginal sponge: 18% to 28%

Condom alone: 12%

Periodic abstinence: 20%

Injectable progestogen: 0.3% to 0.4%

Implants: 0.03% to 0.04%

No methods: 85%.

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES

21-DAY

(Norethindrone and Ethinyl Estradiol Tablets, USP)

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, have a failure rate of about 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3% per year when women who miss pills are included.

Oral contraceptive use is associated with certain serious diseases that can be life-threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you:

• Smoke
• Have high blood pressure, diabetes, high cholesterol
• 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 suspect you are pregnant or have unexplained vaginal bleeding.

28-DAY

(Norethindrone and Ethinyl Estradiol Tablets, USP)

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, have a failure rate of about 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3% per year when women who miss pills are included.

Oral contraceptive use is associated with certain serious diseases that can be life-threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you:

• Smoke
• Have high blood pressure, diabetes, high cholesterol
• 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 suspect you are pregnant or have unexplained vaginal bleeding.

28-DAY

(Norethindrone and Ethinyl Estradiol Tablets, USP)

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, have a failure rate of about 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3% per year when women who miss pills are included.

Oral contraceptive use is associated with certain serious diseases that can be life-threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you:

• Smoke
• Have high blood pressure, diabetes, high cholesterol
• 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 suspect you are pregnant or have unexplained vaginal bleeding.