Ortho-cept Description

ORTHO-CEPT Tablets provide an oral contraceptive regimen of 21 light orange round tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en- 20-yn-17-ol) and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17,diol). Inactive ingredients include colloidal silicone dioxide, corn starch, ferric oxide, lactose, hypromellose, lactose, polyethylene glycol, povidone, stearic acid, talc, titanium dioxide, and vitamin E. Each green tablet contains the following inactive ingredients: FD&C Blue No.1 Aluminum Lake, ferric oxide, hypromellose, lactose, magnesium stearate, polyethylene glycol, pregelatinized starch, talc and titanium dioxide.

Ortho-cept Indications And Usage

ORTHO-CEPT Tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

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

In a clinical trial with ORTHO-CEPT, 1,195 subjects completed 11,656 cycles and a total of 10 pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy) pregnancy rate of 1.12 per 100 women-years. This rate includes patients who did not take the drug correctly.

ORTHO-CEPT has not been studied for and is not indicated for use in emergency contraception.

Ortho-cept Contraindications

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

• Thrombophlebitis or thromboembolic disorders
• A past history of deep vein thrombophlebitis or thromboembolic disorders
• Cerebral vascular or coronary artery disease (current or history)
• Valvular heart disease with complications
• Severe hypertension
• Diabetes with vascular involvement
• Headaches with focal neurological symptoms
• 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
• Acute or chronic hepatocellular disease with abnormal liver function
• Hepatic adenomas or carcinomas
• Known or suspected pregnancy
• Hypersensitivity to any component of this product

Ortho-cept Side Effects

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.

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.

The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with formulations of higher doses of estrogens and progestogens than those in common use today. The effect of long term use of the oral contraceptives with formulations of lower doses of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (Adapted from refs. 2 and 3 with the author's permission). For further information, the reader is referred to a text on epidemiological methods.

1. Thromboembolic Disorder and Other Vascular Problems

A. 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.2,3,19-24 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.25 The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped.2

Several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives. In general, these studies indicate an approximate 2-fold increased risk, which corresponds to an additional 1-2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this 2-fold increase in risk.

A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives.9 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.26 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 weeks after delivery in women who elect not to breast feed.

B. 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.4-10 The risk is very low in women 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.11 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older and in nonsmokers over the age of 40 among women who use oral contraceptives. (See Table II)

TABLE II. CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE (Adapted from P.M. Layde and V. Beral, ref # 12.)

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.14-18 Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

There is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater. Receptor binding and animal studies have shown that desogestrel or its active metabolite has minimal androgenic activity (see CLINICAL PHARMACOLOGY), although these findings have not been confirmed in adequate and well-controlled clinical trials.

C. Cerebrovascular Diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.27-29

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.30 The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.30 The attributable risk is also greater in older women.3

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.31-33 A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.14-16 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 contraceptives. 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 the lowest estrogen content which is judged appropriate for the individual patient.

E. Persistence Of Risk Of Vascular Disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.8 In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.34 However, both studies were performed with oral contraceptive formulations containing 0.050 mg or higher of estrogens.

2. Estimates Of Mortality From Contraceptive Use

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table III). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth.

The observation of an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's.35 Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risk may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also 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. The Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks.

Of course, older women, as all women who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs.

3. Carcinoma Of The Reproductive Organs and Breasts

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives.

The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However, this excess risk appears to decrease over time after discontinuation of combination oral contraceptives and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have found a small increase in risk for women who first use combination oral contraceptives before age 20. Most studies show a similar pattern of risk with combination oral contraceptives regardless of a woman's reproductive history or her family breast cancer history.

Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in nonusers.

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

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.45-48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established.

4. Hepatic Neoplasia

Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.50,51

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. Ocular Lesions

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

6. Oral Contraceptive Use Before Or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.56-57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned,55,56,58,59 when oral contraceptives are 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. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed.

7. Gallbladder Disease

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens.60,61 More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.62-64 The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

8. Carbohydrate and Lipid Metabolic Effects

Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.17 This effect has been shown to be directly related to estrogen dose.65 In general, progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.17,66 In the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic women should be carefully monitored while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1.a. and 1.d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

9. Elevated Blood Pressure

Women with significant hypertension should not be started on hormonal contraception.98 An increase in blood pressure has been reported in women taking oral contraceptives68 and this increase is more likely in older oral contraceptive users69 and with extended duration of use.61 Data from the Royal College of General Practitioners12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity and concentrations of progestogens.

Women with a history of hypertension or hypertension-related diseases, or renal disease70 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,69 and there is no difference in the occurrence of hypertension among former and never users.68,70,71

10. Headache

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

11. Bleeding Irregularities

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

Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.

12. Ectopic Pregnancy

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

Ortho-cept Precautions

1. General

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

2. Physical Examination and Follow-up

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

3. Lipid Disorders

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

4. Liver Function

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

5. Fluid Retention

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

6. Emotional Disorders

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

7. Contact Lenses

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

8. Drug Interactions

Changes In Contraceptive Effectiveness Associated With Co-administration Of Other Products

Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin and bosentan. Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and tetracyclines. However, clinical pharmacology studies investigating drug interaction between combined oral contraceptives and these antibiotics have reported inconsistent results.

Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors. Healthcare professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.

Concurrent use of bosentan and ethinyl estradiol containing products may result in decreased concentrations of these contraceptive hormones thereby increasing the risk of unintended pregnancy and unscheduled bleeding.

Increase In Plasma Levels Associated With Co-administered Drugs

Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels.

Changes In Plasma Levels Of Co-administered Drugs

Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid, due to induction of conjugation, have been noted when these drugs were administered with oral contraceptives.

9. Interactions With Laboratory Tests

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

• Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
• Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
• Other binding proteins may be elevated in serum.
• Sex hormone binding globulins are increased and result in elevated levels of total circulating sex steroids however, free or biologically active levels either decrease or remain unchanged.
• Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.
• 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.

10. Carcinogenesis

See WARNINGS section.

11. Pregnancy

Pregnancy Category X

See CONTRAINDICATIONS and WARNINGS sections.

12. Nursing Mothers

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

13. Pediatric Use

Safety and efficacy of ORTHO-CEPT Tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

14. Geriatric Use

This product has not been studied in women over 65 years of age and is not indicated in this population.

Ortho-cept Overdosage

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

Ortho-cept Supplemental Patient Material

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.

PLEASE NOTE : This labeling is revised from time to time as important new medical information becomes available. Therefore, please review this labeling carefully.

The following oral contraceptive product contains a combination of a progestogen and estrogen, the two kinds of female hormones:

ORTHO-CEPT® (desogestrel and ethinyl estradiol) Tablets

Each light orange tablet contains 0.15 mg desogestrel and 0.03 mg ethinyl estradiol. Each green tablet contains inert ingredients.

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. This patient labeling 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 labeling is not a replacement for a careful discussion between you and your healthcare professional. You should discuss the information provided in this labeling 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 most other non-surgical methods of birth control. When they are taken correctly without missing any pills, the chance of becoming pregnant is approximately 1% (1 pregnancy per 100 women per year of use). Typical failure rates, including women who do not always take the pills exactly as directed, are approximately 5% per year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle.

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES

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

Some women should not use the pill. For example, you should not take the pill if you have any of the following conditions:

• A history of heart attack or stroke
• 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 or vagina
• Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare professional)
• Yellowing of the whites of the eyes or of the skin (jaundice) duringpregnancy or during previous use of the pill
• Liver tumor (benign or cancerous)
• Known or suspected pregnancy
• If you plan to have surgery with prolonged bedrest

Tell your healthcare professional if you have ever had any of these conditions. Your healthcare professional can recommend another method of birth control.

OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES

Tell your healthcare professional if you have or have had:

• Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram
• Diabetes
• Elevated cholesterol or triglycerides
• High blood pressure
• Migraine or other headaches or epilepsy
• Mental 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 professional if they choose to use oral contraceptives.

Also, be sure to inform your healthcare professional 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 one of 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. The risks of these side effects may be greater with desogestrel-containing oral contraceptives, such as ORTHO-CEPT, than with certain other low-dose pills. 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 professional 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 breast feeding. If you are breast feeding, you should wait until you have weaned your child before using the pill. (See also the section on Breast Feeding in General Precautions.)

The risk of circulatory disease in oral contraceptive users may be higher in users of high dose pills. The risk of venous thromboembolic disease associated with oral contraceptives does not increase with length of use and disappears after pill use is stopped. 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 serious disability.

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

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, some studies report an increased risk of developing liver cancer. However, liver cancers are rare.

5. Cancer of the Reproductive Organs and Breasts

Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You should have regular breast examinations by a healthcare professional and examine your own breasts monthly. Tell your healthcare professional 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 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 pills may cause such cancers.

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

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 (7-26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death is 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 do not smoke should not take oral contraceptives is based on information from older, higher-dose pills. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of low-dose oral contraceptive use by healthy, non-smoking 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 progestogen that is compatible with the individual patient needs.

WARNING SIGNALS

If any of these adverse effects occur while you are taking oral contraceptives, call your healthcare professional 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 professional to show you how to examine your breasts)
• Severe pain or tenderness in the stomach area (indicating a possibly 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

1. Vaginal Bleeding

Irregular vaginal bleeding or spotting may occur while you are taking the pills. 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 professional.

2. Contact Lenses

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

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 professional.

4. Melasma

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

5. Other Side Effects

Other side effects may include nausea and vomiting, change in appetite, 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 professional.

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 professional before doing so. If you have not taken the pills daily as instructed and missed a menstrual period, you may be pregnant. If you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare professional immediately to determine whether you are pregnant. Stop taking oral contraceptives if pregnancy is confirmed.

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 findings have not been seen in more recent studies. Nevertheless, oral contraceptives should not be used during pregnancy. You should check with your healthcare professional about risks to your unborn child of any medication taken during pregnancy.

2. While Breast Feeding

If you are breast feeding, consult your healthcare professional 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 breast feeding. You should use another method of contraception since breast feeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breast feed 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 professional 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); topiramate (TOPAMAX® ), carbamazepine (Tegretol® is one brand of this drug), phenytoin (Dilantin® is one brand of this drug); phenylbutazone (Butazolidin® is one brand); certain drugs used in the treatment of HIV or AIDS; and possibly certain antibiotics. Medicine for pulmonary hypertension, such as bosentan (Tracleer® ). Pregnancies and breakthrough bleeding have been reported by women who used some form of the herbal supplement St. John's Wort while using combined hormonal contraceptives. You may need to use additional contraception when you take other products which can make oral contraceptives less effective. Be sure to tell your healthcare professional if you are taking or start taking any medications while taking birth control pills.

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 THE PILL

BEFORE YOU START TAKING YOUR PILLS:

• BE SURE TO READ THESE DIRECTIONS:
  Before you start taking your pills.
  Anytime you are not sure what to do.
• THE RIGHT WAY TO TAKE THE PILL IS TO 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.
• MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you 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 professional.
• 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.
• IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your pills may not work as well.
  Use a back-up method (such as condoms or spermicides) until you check with your healthcare professional.
• IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill-taking easier or about using another method of birth control.
• IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional.

BEFORE YOU START TAKING YOUR PILLS

• DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
  It is important to take it at about the same time every day.
• LOOK AT YOUR PILL PACK:
  The pill pack has 21 light orange "active" pills (with hormones) to take for 3 weeks, followed by 1 week of green "reminder" pills (without hormones).
• ALSO FIND:
  • where on the pack to start taking pills,
  • in what order to take the pills.
  CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.
• BE SURE YOU HAVE READY AT ALL TIMES:
  ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicides) to use as a back-up method in case you miss pills.
  AN EXTRA, FULL PILL PACK.

You have a choice of which day to start taking your first pack of pills. ORTHO-CEPT is available in the DIALPAK® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day which will be easy to remember.

DAY 1 START:

• Take the first light orange "active" pill of the first pack during the first 24 hours of your period.
• 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:

• Take the first light orange "active" 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.
• Use another method of birth control such as condoms or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days).

• 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.
• WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:
  Start the next pack on the day after your last green "reminder" pill. Do not wait any days between packs.

If you MISS 1 light orange "active" pill:

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

If you MISS 2 light orange "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:

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

If you MISS 2 light orange "active" pills in a row in THE 3RD WEEK :

• 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.
• 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 professional because you might be pregnant.
• You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicides) as a back-up method for those 7 days.

If you MISS 3 OR MORE light orange "active" pills in a row (during the first 3 weeks):

• 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.
• You may not have your period this month but this is expected. However, if ou miss your period 2 months in a row, call your healthcare professional because you might be pregnant.
• You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicides) as a back-up method for those 7 days.

Tags: Ortho-cept 0.15mg;0.03mg, Ortho-cept, Sterilization, Contraception, Ethinyl Estradiol, Tablets