Alyacen 7 / 7 / 7

Ethinyl estradiol and norethindrone is a combination drug that contains female hormones that prevent ovulation (the release of an egg from an ovary). This medication also causes changes in your cervical mucus and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus.

Ethinyl estradiol and norethindrone is used as contraception to prevent pregnancy.

Ethinyl estradiol and norethindrone may also be used for purposes not listed in this medication guide.

Do not use birth control pills if you are pregnant or if you have recently had a baby.

You should not take birth control pills if you have any of the following conditions: uncontrolled high blood pressure, heart disease, a blood-clotting disorder, circulation problems, diabetic problems with your eyes or kidneys, unusual vaginal bleeding, liver disease or liver cancer, severe migraine headaches, or if you have ever had breast or uterine cancer, jaundice caused by birth control pills, a heart attack, a stroke, or a blood clot.

Taking birth control pills can increase your risk of blood clots, stroke, or heart attack, especially if you have certain other conditions, or if you are overweight.

Smoking can increase your risk of blood clot, stroke, or heart attack while taking birth control pills. You should not take ethinyl estradiol and norethindrone if you smoke and are older than 35 years of age.

Taking birth control pills can increase your risk of blood clots, stroke, or heart attack. You are even more at risk if you have high blood pressure, diabetes, high cholesterol, or if you are overweight. Your risk of stroke or blood clot is highest during your first year of taking birth control pills. Your risk is also high when you restart birth control pills after not taking them for 4 weeks or longer.

Smoking can greatly increase your risk of blood clots, stroke, or heart attack. Your risk increases the older you are and the more you smoke. You should not take combination birth control pills if you smoke and are over 35 years old.

Do not use if you are pregnant or think you might be pregnant. Tell your doctor right away if you become pregnant, or if you miss two menstrual periods in a row. If you have recently had a baby, wait at least 4 weeks before taking birth control pills.

You should not take birth control pills if you have:

• untreated or uncontrolled high blood pressure;
• heart disease (coronary artery disease, uncontrolled heart valve disorder, history of heart attack, stroke, or blood clot);
• a blood-clotting disorder or circulation problems;
• problems with your eyes, kidneys or circulation caused by diabetes;
• a history of hormone-related cancer such as breast or uterine cancer;
• unusual vaginal bleeding that has not been checked by a doctor;
• liver disease or liver cancer;
• severe migraine headaches (with aura, numbness, weakness, or vision changes), especially if you are older than 35;
• a history of jaundice caused by pregnancy or birth control pills; or
• if you smoke and are over 35 years old.

To make sure birth control pills are safe for you, tell your doctor if you have:

• high blood pressure, varicose veins;
• high cholesterol or triglycerides, or if you are overweight;
• a history of depression;
• underactive thyroid;
• gallbladder disease;
• diabetes;
• seizures or epilepsy;
• a history of irregular menstrual cycles;
• tuberculosis; or
• a history of fibrocystic breast disease, lumps, nodules, or an abnormal mammogram.

The hormones in birth control pills can pass into breast milk and may harm a nursing baby. This medication may also slow breast milk production. Do not use if you are breast feeding a baby.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using this medicine and call your doctor at once if you have:

• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;
• signs of a blood clot--chest pain, sudden cough, wheezing, coughing up blood, swelling or warmth in one or both legs;
• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;
• vision changes;
• a change in the pattern or severity of migraine headaches;
• swelling in your hands, ankles, or feet;
• a breast lump; or
• symptoms of depression--sleep problems, weakness, tired feeling, mood changes.

Common side effects may include:

• nausea, vomiting;
• breast tenderness or swelling;
• freckles or darkening of facial skin, increased hair growth, loss of scalp hair;
• changes in weight or appetite;
• problems with contact lenses;
• vaginal itching or discharge; or
• changes in your menstrual periods, decreased sex drive.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Do not smoke while taking birth control pills, especially if you are older than 35 years of age.

Birth control pills will not protect you from sexually transmitted diseases--including HIV and AIDS. Using a condom is the only way to protect yourself from these diseases.

Some drugs can make birth control pills less effective, which may result in pregnancy. Other drugs may be affected by birth control pills. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with ethinyl estradiol and norethindrone. Give a list of all your medicines to any healthcare provider who treats you.

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives, including ALYACEN 7/7/7 and ALYACEN 1/35, should not be used by women who are over 35 years of age and 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 higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.

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

1. Thromboembolic Disorders and Other Vascular Problems

a. Myocardial Infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.4–10 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.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 Figure 1).

Figure 1. Circulatory Disease Mortality Rates per 100,000 Women-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 10 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

b. Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers 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 gradually disappears after combined oral contraceptive (COC) use is stopped.2 VTE risk is highest in the first year of use and when restarting hormonal contraception after a break of four weeks or longer.

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 breastfeed.

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 activity of the progestogen used in the contraceptives. The activity and 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 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 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). 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 risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are 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.

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

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

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 COCs. However, this excess risk appears to decrease over time after COC discontinuation 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 COCs before age 20. Most studies show a similar pattern of risk with COC use regardless of a woman's reproductive history or her family breast cancer history.

Breast cancers diagnosed in current or previous OC 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. 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 ALYACEN 7/7/7 and ALYACEN 1/35 prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS). ALYACEN 7/7/7 and ALYACEN 1/35, 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.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 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.

8. 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.

9. 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 Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.17,66 However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic women in particular 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 WARNINGS1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

10. Elevated Blood Pressure

Women with significant hypertension should not be started on hormonal contraception.92 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.

Women with a history of hypertension or hypertension-related diseases, or renal disease70 should be encouraged to use another method of contraception. If these women elect to use oral contraceptives, they should be monitored closely and if a clinically significant persistent elevation of blood pressure (BP) occurs (≥ 160 mm Hg systolic or ≥ 100 mm Hg diastolic) and cannot be adequately controlled, oral contraceptives should be discontinued. In general, women who develop hypertension during hormonal contraceptive therapy should be switched to a non-hormonal contraceptive. If other contraceptive methods are not suitable, hormonal contraceptive therapy may continue combined with antihypertensive therapy. Regular monitoring of BP throughout hormonal contraceptive therapy is recommended.96 For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension between former and never users.68–71

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.

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

13. Ectopic Pregnancy

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

The following non-contraceptive health benefits related to the use of combined 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 mestranol.73–78

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

Other effects:

• 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

Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, nonfunctional causes should be borne in mind. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease.

Use of oral contraceptives in the event of a missed menstrual period:

1. 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 and oral contraceptive use should be discontinued if pregnancy is confirmed. 2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out.

ALYACEN 7/7/7 Tablets are available in blister packs containing 28 tablets, as follows:

• 7 white to off-white, round, flat faced, beveled edged, uncoated tablets debossed with ‘A4’ on one side and plain on the other. Each white to off-white tablet contains 0.5 mg norethindrone, USP and 0.035 mg ethinyl estradiol, USP; • 7 light peach, round, flat faced, beveled edged uncoated tablets debossed with ‘A3’ on one side and plain on the other. Each light peach tablet contains 0.75 mg norethindrone, USP and 0.035 mg ethinyl estradiol, USP; • 7 peach, round, flat faced, beveled edged uncoated tablets debossed with ‘A1’ on one side and plain on the other. Each peach tablet contains 1 mg norethindrone, USP and 0.035 mg ethinyl estradiol, USP; and • 7 light green, round, flat faced, beveled edged uncoated tablets debossed with ‘A2’ on one side and plain on the other. Each light green tablet contains inert ingredients.

NDC 68462-556-29 1 carton containing 3 blister cards of 28 tablets

ALYACEN 1/35 Tablets are available in blister packs containing 28 tablets, as follows:

• 21 peach, round, flat faced, beveled edged uncoated tablets, debossed with ‘A1’ on one side and plain on the other. Each peach tablet conains 1 mg norethindrone, USP and 0.035 mg ethinyl estradiol, USP; and • 7 light green, round, flat faced, beveled edged uncoated tablets debossed with ‘A2’ on one side and plain on the other. Each light green tablet contains inert ingredients.

NDC 68462-394-29 1 carton containing 3 blister cards of 28 tablets

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Keep out of reach of children.

Trademarks are the property of their respective owners.

Some studies have examined the effect of progestin-only contraceptives on breast-feeding. The extent to which such studies have bearing on oral contraceptive combinations is uncertain. Use of such formulations have not been associated with deleterious effects on breast-fed infants.

Both the estrogens and progestins occurring in commercially available oral formulations are excreted into human milk in very small amounts. The American Academy of Pediatrics considers use of oral contraceptive combinations to be compatible with breast-feeding despite rare reports of breast enlargement in the nursing infant and the possibility of a decrease in milk production and protein content. The manufacturer recommends that caution be used when administering ethinyl estradiol-norethindrone to nursing mothers.