Pharmacokinetics

Absorption

Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are rapidly absorbed, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 2 hours post-dose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol.

Administration of norethindrone acetate and ethinyl estradiol with a high fat meal decreases rate, but not extent, of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27% following administration with food.

Plasma concentrations of norethindrone and ethinyl estradiol following chronic administration of norethindrone acetate and ethinyl estradiol tablets to 17 women are shown below (Figure 1). Mean steady-state concentrations of norethindrone for the 1/20, 1/30, and 1/35 tablet strengths increased as ethinyl estradiol dose increased over the 21-day dose regimen, due to dose-dependent effects of ethinyl estradiol on serum SHBG concentrations (Table 1). Mean steady-state plasma concentrations of ethinyl estradiol for the 1/20, 1/30, and 1/35 tablet strengths were proportional to ethinyl estradiol dose (Table 1).

Figure 1. Mean Steady-State Plasma Ethinyl Estradiol and Norethindrone Concentrations Following Chronic Administration of Norethindrone Acetate and Ethinyl Estradiol Tablets

* Cmax = Maximum plasma concentration; AUC (0-24) = Area under the plasma concentration-time curve over the dosing interval; CL/F = Apparent oral clearance

† Mean (SD) baseline value = 55 (29) nmol/L

No age-related differences were seen in plasma concentrations of ethinyl estradiol and norethindrone following administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets to 119 postmenarchal women ages 15 to 48 years.

Distribution

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (> 95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis. Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets increase serum SHBG concentrations two- to three-fold (Table 1).

Metabolism

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation.

Excretion

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are approximately 13 hours and 19 hours, respectively.

SPECIAL POPULATION

Race

The effect of race on the disposition of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets has not been evaluated.

Renal Insufficiency

The effect of renal disease on the disposition of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of a combined oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.

Hepatic Insufficiency

The effect of hepatic disease on the disposition of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function.

Drug-Drug Interactions

Numerous drug-drug interactions have been reported for combined oral contraceptives. A summary of these is found under PRECAUTIONS, Drug Interactions.

The use of combined 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 combined 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 combined oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the combined 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 combined 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 combined oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from References 8 and 9 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 combined 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 combined oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.

Smoking in combination with combined oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Figure 3) among women who use combined oral contraceptives.

Figure 3. Circulatory Disease Mortality Rates per 100,000 Woman Years by Age, Smoking Status and Combined Oral Contraceptive Use

Adapted from P.M. Layde and V. Beral

Combined oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Combined 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. Combined oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

2. Estimates of Mortality from Combined Oral 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 4). 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 combined 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 combined oral contraceptive users is based on data gathered in the 1970’s but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of combined oral contraceptive use to women who do not have the various risk factors listed in this labeling.

Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of combined 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, Hershel J, 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 risks may be increased with combined 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 combined oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take combined oral contraceptives, should take the lowest possible dose formulation that is effective.

** Deaths are method-related.

Adapted from H.W. Ory, Reference 41.

3. Malignant Neoplasms

Breast Cancer

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive (see Contraindications).

Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use (see Post Marketing Experience).

Cervical Cancer

Some studies suggest that combined 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.

4. Hepatic Neoplasia

Benign hepatic adenomas are associated with combined 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 4 or more years of use. Rupture of rare, benign, 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) combined oral contraceptive users. However, these cancers are extremely rare in the US, and the attributable risk (the excess incidence) of liver cancers in combined 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see Contraindications). Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 combined oral contraceptives. Combined 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 and During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used combined oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy.

The administration of combined oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Combined 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. Combined 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 combined 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 combined oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

9. Carbohydrate and Lipid Metabolic Effects

Combined oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Combined oral contraceptives containing greater than 75 mcg 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 non-diabetic woman, combined 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 combined oral contraceptives.

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

10. Elevated Blood Pressure

An increase in blood pressure has been reported in women taking combined oral contraceptives and this increase is more likely in older combined 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 combined oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, combined oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping combined oral contraceptives, and there is no difference in the occurrence of hypertension among ever and never users.

11. Headache

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

12. Bleeding Irregularities

Breakthrough bleeding and spotting are sometimes encountered in patients on combined oral contraceptives, especially during the first three months of use. Non-hormonal causes should be considered, and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of prolonged 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.Hereditary Angioedema

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

14. Chloasma

Chloasma may occur with norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, especially in women with a history of chloasma gravidarum. Advise women with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets.

1. 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 combined oral contraceptives. The physical examination, however, may be deferred until after initiation of combined 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 hyperlipidemia should be followed closely if they elect to use combined 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 such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.

5. Fluid Retention

Combined 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

Effects of Other Drugs on Combined Oral Contraceptives

Rifampin: Metabolism of both norethindrone and ethinyl estradiol is increased by rifampin. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin.

Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine, have been shown to increase the metabolism of ethinyl estradiol and/or norethindrone, which could result in a reduction in contraceptive effectiveness.

Antibiotics: Pregnancy while taking combined oral contraceptives has been reported when the combined oral contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.

Atorvastatin: Coadministration of atorvastatin and an combined oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively.

St. John’s Wort: 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 combined oral contraceptives. This may also result in breakthrough bleeding.

Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors

Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation: Do not co-administer norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see Warnings, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT).

Other: Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding has been suggested with phenylbutazone.

Effects of Combined Oral Contraceptives on Other Drugs

COCs containing ethinyl estradiol may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increase with use of COCs.

9. Interactions with Laboratory Tests

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

a.

Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.

b.

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.

c.

Other binding proteins may be elevated in serum.

d.

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.

e.

Triglycerides may be increased.

f.

Glucose tolerance may be decreased.

g.

Serum folate levels may be depressed by combined oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing combined oral contraceptives.

10. Carcinogenesis

See WARNINGS section.

11. Pregnancy

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, combined 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 combined oral contraceptives but to use other forms of contraception until she has completely weaned her child.

13. Pediatric Use

Safety and efficacy of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate 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.

INFORMATION FOR THE PATIENT

See patient labeling printed below.

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

The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill:

1.

Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris), or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences.

2.

Liver tumors, which may rupture and cause severe bleeding. A possible but not definite association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer.

3.

High blood pressure, although blood pressure usually returns to normal when the pill is stopped.

The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your doctor or healthcare provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, may decrease combined oral contraceptive effectiveness.

Do not take the pill if you take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme “alanine aminotransferase” (ALT) in the blood.

There may be slight increases in the risk of breast cancer among current users of hormonal birth control pills with longer duration of use of 8 years or more.

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

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

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

INSTRUCTIONS TO PATIENT

TABLET BLISTER

The norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets blister has been designed to make combined oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in four rows of seven tablets each, with the days of the week appearing above the first row of tablets.

Each white to off white tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.

Each light purple tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol.

Each purple tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol.

Each brown tablet contains 75 mg ferrous fumarate and is intended to help you remember to take the tablets correctly. These brown tablets are not intended to have any health benefit.

DIRECTIONS

To remove a tablet, press down on it with your thumb or finger. The tablet will drop through the back of the tablet blister. Do not press with your thumbnail, fingernail, or any other sharp object.

HOW TO TAKE THE PILL

BEFORE YOU START TAKING YOUR PILLS:

1.

BE SURE TO READ THESE DIRECTIONS:

 

Before you start taking your pills.

 

Anytime you are not sure what to do.

2.

THE 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.

3.

MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH, DURING THE FIRST 1-3 PACKS OF PILLS. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your doctor or clinic.

4.

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.

5.

IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use a back-up birth control method (such as condoms or spermicide) until you check with your doctor or clinic.

6.

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

7.

IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic.

1.      DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day.

2.      LOOK AT YOUR PILL PACK: The pill pack has 21 “active“ pills (with hormones) to take for 3 weeks, followed by 1 week of “reminder” brown pills (without hormones).

3.      ALSO FIND:

           1)    where on the pack to start taking pills,

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

           3)    the week numbers as shown in the following pictures:

Each norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets blister contains five white to off white tablets, seven light purple tablets, nine purple tablets, and seven brown tablets. These tablets are to be taken in the following order: one white to off white tablet each day for five days, then one light purple tablet each day for seven days, followed by one purple tablet each day for nine days, and then one brown tablet each day for seven days.

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets will contain: 5 WHITE TO OFF WHITE, 7 LIGHT PURPLE, 9 PURPLE PILLS for Weeks 1, 2, and 3. Week 4 will contain BROWN PILLS ONLY.

4.     BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a back-up 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. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember.

DAY-1 START:

1.

Pick the day label strip that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.)

2.

Place this day label strip on the tablet blister over the area that has the days of the week (starting with Sunday) printed on the plastic.

3.

Take the first "active" white to off white pill of the first pack during the first 24 hours of your period.

4.

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

SUNDAY START:

1.

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

2.

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

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

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

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

2.      WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:

         21 pills: Wait 7 days to start the next pack. You will probably have your period during that week. Be sure that no more than 7 days pass between 21-day packs.

 

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

If you MISS 1 white to off white “active” pill:

1.

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

2.

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

If you MISS 2 white to off white “active” pills in a row in Week 1 OR light purple “active” pills in Week 2 of your pack:

1.

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

2.

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

3.

You COULD GET PREGNANT if you have sex in the 7 days after you miss pills.You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white to off white “active” pill every day for 7 days.

If you MISS 2 purple “active” pills in a row in THE 3rd WEEK:

1.

If you are a Day-1 Starter:

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

If you are a Sunday Starter:

Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

2.

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

3.

You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white to off white “active” pill every day for 7 days.

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

1.

If you are a Day-1 Starter:

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

If you are a Sunday Starter:

Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

1.

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 doctor or clinic because you might be pregnant.

2.

You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white to off white “active” pill every day for 7 days.

Based on his or her assessment of your medical needs, your doctor or healthcare provider has prescribed this drug for you. Do not give this drug to anyone else.

Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]

Protect from light.

Store tablets in blister sleeve when not in use.

Keep this and all medication out of the reach of children.

Rx only

DETAILED PATIENT PACKAGE INSERT

What is the most important information I should know about norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets?

Do not use norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets (like all oral contraceptives) are intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases.

What You Should Know About Combined Oral Contraceptives

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 leaflet will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this leaflet is not a replacement for a careful discussion between you and your healthcare provider. You should discuss the information provided in this leaflet with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare provider’s advice with regard to regular check-ups while you are on the pill.

EFFECTIVENESS OF COMBINED 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. When they are taken correctly, the chance of becoming pregnant is less than 1% (1 pregnancy per 100 women per year of use) when used perfectly, without missing any pills. Typical failure rates are actually 5% per year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle.

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

Implant: < 1%

Injection: < 1%

IUD: < 1 to 2%

Diaphragm with spermicides: 20%

Spermicides alone: 26%

Vaginal Sponge: 20 to 40%

Female sterilization: < 1%

Male sterilization: < 1%

Cervical Cap: 20 to 40%

Condom alone (male): 14%

Condom alone (female): 21%

Periodic abstinence: 25%

Withdrawal: 19%

No method: 85%

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may also be taken to treat moderate acne if all of the following are true:

•

Your doctor says it is safe for you to use the pill

•

You are at least 15 years old

•

You have started having menstrual periods

•

You want to use the pill for birth control

•

You plan to stay on the pill for at least 6 months

•

Your acne has not improved with acne medicines that you put on your skin

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets users who started with about 74 acne pimples had about 42 pimples after 6 months of treatment. Placebo users who started with about 72 acne pimples had about 49 pimples after six months of treatment. Use norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets to treat acne only if you want the pill for birth control and plan to stay on it for at least 6 months.

WHO SHOULD NOT TAKE COMBINED ORAL CONTRACEPTIVES?

HOW TO TAKE THE PILL

BEFORE YOU START TAKING YOUR PILLS:

1.      BE SURE TO READ THESE DIRECTIONS:

        Before you start taking your pills.

        Anytime you are not sure what to do.

2.      THE 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.

3.      MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH, DURING THE FIRST 1-3 PACKS OF PILLS. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your doctor or clinic.

4.   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.

5.      IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use a back-up birth control method (such as condoms or spermicide) until you check with your doctor or clinic.

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

7.      IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic.

1.      DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day.

2.      LOOK AT YOUR PILL PACK. The pill pack has 21 “active” pills (with hormones) to take for 3 weeks, followed by 1 week of “reminder” brown pills (without hormones).

3.      ALSO FIND:

           1)    where on the pack to start taking pills,

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

           3)    the week numbers as shown in the following pictures:

Each norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets blister contains five white to off white tablets, seven light purple tablets, nine purple tablets, and seven brown tablets. These tablets are to be taken in the following order: one white to off white tablet each day for five days, then one light purple tablet each day for seven days, followed by one purple tablet each day for nine days, and then one brown tablet each day for seven days.

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets will contain: 5 WHITE TO OFF WHITE, 7 LIGHT PURPLE, 9 PURPLE PILLS for Weeks 1, 2, and 3.Week 4 will contain BROWN PILLS ONLY.

4.      BE SURE YOU HAVE READY AT ALL TIMES:

        ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a back-up 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. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember.

DAY-1 START:

1.

Pick the day label strip that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.)

2.

Place this day label strip on the tablet blister over the area that has the days of the week (starting with Sunday) printed on the plastic.

3.

Take the first “active” white to off white pill of the first pack during the first 24 hours of your period.

4.

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

SUNDAY START:

1.

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

2.

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

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

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

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

2.      WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:

         21 pills: Wait 7 days to start the next pack. You will probably have your period during that week. Be sure that no more than 7 days pass between 21-day packs.

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

If you MISS 1 white to off white “active” pill:

1.

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

2.

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

If you MISS 2 white to off white  “active” pills in a row in Week 1 OR light purple “active” pills in Week 2 of your pack:

1.

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

2.

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

3.

You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white to off white “active” pill every day for 7 days.

If you MISS 2 purple  “active”  pills in a row in THE 3rd WEEK:

1.      If you are a Day-1 Starter:

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

        If you are a Sunday Starter:

        Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

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

3.      You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white to off white  “active” pill every day for 7 days.

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

1.      If you are a Day-1 Starter:

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

        If you are a Sunday Starter:

        Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

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

3.      You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white to off white “active” pill every day for 7 days.

PREGNANCY DUE TO PILL FAILURE

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

PREGNANCY AFTER STOPPING THE PILL

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

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

OVERDOSAGE

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

OTHER INFORMATION

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

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

HEALTH BENEFITS FROM COMBINED ORAL CONTRACEPTIVES

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

•

Menstrual cycles may become more regular.

•

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

•

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

•

Ectopic (tubal) pregnancy may occur less frequently.

•

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

•

Acute pelvic inflammatory disease may occur less frequently.

•

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

If you want more information about birth control pills, ask your doctor or pharmacist. They have a more technical leaflet called the “Physician Insert”, which you may wish to read.

Remembering to take tablets according to schedule is stressed because of its importance in providing you the greatest degree of protection.

MISSED MENSTRUAL PERIODS

At times there may be no menstrual period after a cycle of pills. Therefore, if you miss one menstrual period but have taken the pills exactly as you were supposed to, continue as usual into the next cycle. If you have not taken the pills correctly and miss a menstrual period, you may be pregnant and should stop taking oral contraceptives until your doctor or healthcare provider determines whether or not you are pregnant. Until you can get to your doctor or healthcare provider, use another form of contraception. If two consecutive menstrual periods are missed, you should stop taking pills until it is determined whether or not you are pregnant. Although there does not appear to be any increase in birth defects in newborn babies, if you become pregnant while using oral contraceptives, you should discuss the situation with your doctor or healthcare provider.

Periodic Examination

Your doctor or healthcare provider will take a complete medical and family history before prescribing oral contraceptives. At that time and about once a year thereafter, he or she will generally examine your blood pressure, breasts, abdomen, and pelvic organs (including a Papanicolaou smear, i.e., test for cancer).

Rx only

Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]

Protect from light.

Store tablets in blister sleeve when not in use.

Keep this and all medication out of the reach of children.

To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Manufactured for:

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Manufactured by:

Mylan Laboratories Limited

Ahmedabad - 382 213, India

Code No.: GUJ-DRUGS/G/28/1297

75083624

Revised: 11/2021

FC:OT:7303:R5