FDA filings in the form of structured product labels are documents that include all published material associated whith this product. Product label information includes data like indications and usage generic names, contraindications, active ingredients, strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.
Warning: Cigarette Smoking And Serious Cardiovascular Events
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke [see Contraindications (4)].
1 Indications And Usage
NA/EE and Fe is indicated for use by females of reproductive age to prevent pregnancy [see Clinical Studies (14)].
The efficacy of NA/EE and Fe in women with a body mass index (BMI) of more than 35 kg/m2 has not been evaluated.
2.1 How To Take Na/Ee And Fe Tablets
To achieve maximum contraceptive effectiveness, NA/EE and Fe tablets must be taken exactly as directed. Instruct patients to take one tablet by mouth at the same time every day. The tablet may be chewed and swallowed or swallowed whole. The patient should drink a full glass (8 ounces) of water immediately after the white tablets are chewed or swallowed whole. Tablets must be taken in the order directed on the blister pack. Tablets should not be skipped or taken at intervals exceeding 24 hours. For patient instructions for missed tablets, [see FDA-approved patient labeling]. NA/EE and Fe tablets may be administered without regard to meals [see Clinical Pharmacology (12.3)].
2.2 How To Start Na/Ee And Fe Tablets
Instruct the patient to begin taking NA/EE and Fe tablets either on the first day of her menstrual period (Day 1 Start) or on the first Sunday after the onset of her menstrual period (Sunday Start).
Day 1 Start
During the first cycle of NA/EE and Fe tablet use, instruct the patient to take one white NA/EE and Fe tablet daily, beginning on Day one (1) of her menstrual cycle (the first day of menstruation is Day one). She should take one white NA/EE and Fe tablet daily for 24 consecutive days, followed by one brown tablet daily on days 25 through 28. NA/EE and Fe tablets should be taken in the order directed on the package at the same time each day. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days if she starts taking NA/EE and Fe tablets on a day other than the first day of her menstrual cycle. The possibility of ovulation and conception prior to initiation of medication should be considered.
During the first cycle of NA/EE and Fe tablets use, instruct the patient to take one white NA/EE and Fe tablet daily, beginning on the first Sunday after the onset of her menstrual period. She should take one white NA/EE and Fe tablet daily for 24 consecutive days, followed by one brown tablet daily on days 25 through 28. NA/EE and Fe tablets should be taken in the order directed on the package at the same time each day. NA/EE and Fe tablets should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered.
The patient should begin her next and all subsequent 28-day regimens of NA/EE and Fe tablets on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her white NA/EE and Fe tablets on the next day after ingestion of the last brown tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of NA/EE and Fe tablets is started later than the day following administration of the last brown tablet, the patient should use another method of contraception until she has taken a white NA/EE and Fe tablet daily for 7 consecutive days.
For postpartum women who do not breastfeed or after a second trimester abortion, start NA/EE and Fe tablets no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts on NA/EE and Fe tablets postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken NA/EE and Fe tablets for 7 consecutive days.
NA/EE and Fe tablets may be initiated immediately after a first-trimester abortion or miscarriage; if the patient starts NA/EE and Fe tablets immediately, additional contraceptive measures are not needed.
2.3 Switching From Another Hormonal Method Of Contraception
If the patient is switching from a combination hormonal method such as:
2.4 Advice In Case Of Gastrointestinal Disturbances
If the patient vomits or has diarrhea (within 3 to 4 hours after she takes a white NA/EE and Fe tablet), she should follow the instructions in the “What to Do if You Miss Tablets” section [see FDA-approved patient labeling].
3 Dosage Forms And Strengths
NA/EE and Fe is available in blister packs.
Each blister pack contains 28 tablets in the following order:
- •24 white, round, (active) chewable tablets imprinted with “WC” on one side and “535” on the other side, and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.
- •4 brown, round (non-hormonal placebo) tablets imprinted with “WC” on one side and “624” on the other side, and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.
Do not prescribe NA/EE and Fe tablets to women who are known to have the following conditions:
- •A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:
- •Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)]
- •Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)]
- •Have cerebrovascular disease [see Warnings and Precautions (5.1)]
- •Have coronary artery disease [see Warnings and Precautions (5.1)]
- •Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)]
- •Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)]
- •Have uncontrolled hypertension [see Warnings and Precautions (5.3)]
- •Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.5)]
- •Have headaches with focal neurological symptoms or have migraine headaches with aura
- oAll women over age 35 with migraine headache [see Warnings and Precautions (5.6)]
- •Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.2)]
- •Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.7)]
- •Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]
- •Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.10)]
5.1 Thromboembolic Disorders And Other Vascular Problems
Stop NA/EE and Fe tablets if an arterial or deep venous thrombotic event (VTE) occurs. Stop NA/EE and Fe tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
If feasible, stop NA/EE and Fe tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE.
Start NA/EE and Fe tablets no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COC. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued.
Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. COCs 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 in older (greater than 35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with underlying risk factors.
Use COCs with caution in women with cardiovascular disease risk factors.
5.2 Liver Disease
Impaired Liver Function
Do not use NA/EE and Fe tablets in women with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4)]. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Discontinue NA/EE and Fe tablets if jaundice develops.
NA/EE and Fe is contraindicated in women with benign and malignant liver tumors [see Contraindications (4)]. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases per 100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.
Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (greater than 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.
5.3 High Blood Pressure
NA/EE and Fe is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For women with well-controlled hypertension, monitor blood pressure and stop NA/EE and Fe tablets if blood pressure rises significantly.
An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin.
5.4 Gallbladder Disease
Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may also worsen existing gallbladder disease.
A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.
5.5 Carbohydrate And Lipid Metabolic Effects
Carefully monitor prediabetic and diabetic women who are taking NA/EE and Fe tablets. COCs may decrease glucose tolerance in a dose-related fashion.
Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of women will have adverse lipid changes while on COCs.
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.
If a woman taking NA/EE and Fe tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue NA/EE and Fe tablets if indicated.
Consider discontinuation of NA/EE and Fe tablets in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see Contraindications (4)].
5.7 Bleeding Irregularities And Amenorrhea
Unscheduled Bleeding and Spotting
Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.
Based on patient diaries from a clinical trial evaluating the safety and efficacy of a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets, 24-35% of women experienced unscheduled bleeding per cycle. A total of 10 subjects out of 743 (1.3%) discontinued due to bleeding or spotting.
Amenorrhea and Oligomenorrhea
Women who are not pregnant and use norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may experience amenorrhea. In the clinical trial with a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets and ferrous fumarate tablets, 22 to 36% of the women using norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets and ferrous fumarate tablets experienced amenorrhea in at least one of 6 cycles of use. Some women may experience post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent.
If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.
5.8 Coc Use Before Or During Early Pregnancy
Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue NA/EE and Fe tablets if pregnancy is confirmed.
Administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].
Carefully observe women with a history of depression and discontinue NA/EE and Fe tablets if depression recurs to a serious degree.
5.10 Carcinoma Of The Breast And Cervix
NA/EE and Fe is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally-sensitive [see Contraindications (4)].
There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.
Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors.
5.11 Effect On Binding Globulins
The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormones or cortisol therapy may need to be increased.
A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.
5.13 Hereditary Angioedema
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking NA/EE and Fe tablets.
6 Adverse Reactions
The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data presented in Section 6.1 are from a clinical trial conducted with a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets. NA/EE and Fe is bioequivalent to these norethindrone acetate/ethinyl estradiol tablets.
Common Adverse Reactions (Greater Than or Equal to 2% of all Treated Subjects): The most common adverse reactions reported by at least 2% of the 743 women using norethindrone acetate/ethinyl estradiol tablets were the following, in order of decreasing incidence: headache (6.3%), vaginal candidiasis (6.1%), nausea (4.6%), menstrual cramps (4.4%), breast tenderness (3.4%), bacterial vaginitis (3.1%), abnormal cervical smear (3.1%), acne (2.7%), mood swings (2.2%), and weight gain (2.0%).
Adverse Reactions Leading to Study Discontinuation: Among the 743 women using norethindrone acetate/ethinyl estradiol tablets, 46 women (6.2%) withdrew because of an adverse event. Adverse events occurring in 3 or more subjects leading to discontinuation of treatment were, in decreasing order: abnormal or irregular bleeding (1.3%), nausea (0.8%), menstrual cramps (0.5%), and increased blood pressure (0.4%).
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or evaluate a causal relationship to drug exposure.
Adverse reactions are grouped into System Organ Classes.
Vascular disorders: thrombosis/embolism (coronary artery, pulmonary, cerebral, deep vein).
Hepatobiliary disorders: cholelithiasis, cholecystitis, hepatic adenoma, hemangioma of liver.
Immune system disorders: hypersensitivity reaction.
Skin and subcutaneous disorders: alopecia, rash (generalized and allergic), pruritus, skin discoloration.
GI disorders: nausea, vomiting, abdominal pain.
Musculoskeletal and connective tissue disorders: myalgia.
Eye disorders: blurred vision, visual impairment, corneal thinning, change in corneal curvature (steepening).
Infections and infestations: fungal infection, vaginal infection.
Investigations: change in weight or appetite (increase or decrease), fatigue, malaise, peripheral edema, blood pressure increased.
Nervous system disorders: headache, dizziness, migraine, loss of consciousness.
Psychiatric disorders: mood swings, depression, insomnia, anxiety, suicidal ideation, panic attack, changes in libido.
Renal and urinary disorders: cystitis-like syndrome.
Reproductive system and breast disorders: breast changes (tenderness, pain, enlargement, and secretion), premenstrual syndrome, dysmenorrhea.
Cardiovascular: chest pain, palpitations, tachycardia, myocardial infarction.
7 Drug Interactions
Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.
No drug-drug interaction studies were conducted with NA/EE and Fe tablets.
7.1 Effects Of Other Drugs On Combined Oral Contraceptives
Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate and products containing St. John’s wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.
Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone concentrations.
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 the estrogen and progestin have been noted in some cases of co-administration of HIV/HCV protease inhibitors or of non-nucleoside reverse transcriptase inhibitors.
Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.
7.2 Effects Of Combined Oral Contraceptives On Other Drugs
COCs containing ethinyl estradiol may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, 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 serum concentration of thyroid-binding globulin increases with use of COCs.
7.3 Interference With Laboratory Tests
The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.
The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion.
8.3 Nursing Mothers
When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.
8.4 Pediatric Use
Safety and efficacy of NA/EE and Fe tablets have been established in women of reproductive age. Efficacy is expected to be the same in postpubertal adolescents under the age of 18 years as for users 18 years and older. Use of this product before menarche is not indicated.
8.5 Geriatric Use
NA/EE and Fe tablets have not been studied in postmenopausal women and is not indicated in this population.
8.6 Renal Impairment
The pharmacokinetics of NA/EE and Fe tablets has not been studied in subjects with renal impairment.
8.7 Hepatic Impairment
The pharmacokinetics of NA/EE and Fe tablets has not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded [see Contraindications (4) and Warnings and Precautions (5.2)].
8.8 Body Mass Index
The safety and efficacy of NA/EE and Fe tablets in women with a body mass index (BMI) greater than 35 kg/m2 has not been evaluated [see Clinical Studies (14)].
There have been no reports of serious ill effects from overdose of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.
NA/EE and Fe tablets provides an oral contraceptive regimen consisting of 24 white active chewable tablets that contain the active ingredients, followed by 4 brown non-hormonal placebo tablets as specified below:
- •24 white, round tablets each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.
- •4 brown, round tablets each containing 75 mg ferrous fumarate
Each white active chewable tablet also contains the following inactive ingredients: acacia, lactose monohydrate, magnesium stearate, modified starch, confectioner’s sugar, talc, sucralose and spearmint flavor.
Each brown placebo tablet contains ferrous fumarate, mannitol, povidone, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, sucralose and spearmint flavor. The ferrous fumarate tablets do not serve any therapeutic purpose.
The empirical formula of ethinyl estradiol is C20H24O2 and the structural formula is:
The chemical name of ethinyl estradiol is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-]. The molecular weight of ethinyl estradiol is 296.40.
The empirical formula of norethindrone acetate is C22H28O3 and the structural formula is:
The chemical name of norethindrone acetate is [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-]. The molecular weight of norethindrone acetate is 340.46.
12.1 Mechanism Of Action
COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.
No specific pharmacodynamic studies were conducted with NA/EE and Fe tablets.
In a single-dose, two-way, crossover clinical study conducted in 35 healthy, non-smoking premenopausal women under fasting condition, NA/EE and Fe tablet chewed and swallowed was bioequivalent to norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablet (24-day regimen tablets) swallowed whole based on the exposure (AUC) and peak concentration (Cmax) of norethindrone and ethinyl estradiol.
Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, because the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are absorbed from NA/EE and Fe tablets (chewed and swallowed), with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring at 1.0 hr (range: 0.7 to 2.5 hrs) and 1.3 hr (range: 1 to 2.5 hrs) post-dose, respectively. 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.
The plasma norethindrone and ethinyl estradiol pharmacokinetics following single-dose administrations of NA/EE and Fe tablets (chewed and swallowed) in 35 healthy female subjects are provided in Figures 1 and 2, and Table 1.
Following multiple-dose administration of norethindrone acetate/ethinyl estradiol tablets (swallowed whole) in 17 healthy female subjects, mean maximum concentrations of norethindrone and ethinyl estradiol were increased by 95% and 27%, respectively, as compared to single-dose administration. Mean norethindrone and ethinyl estradiol exposures (AUC values) were increased by 164% and 51% respectively, as compared to single-dose administration of norethindrone acetate/ethinyl estradiol tablets.
Steady-state with respect to norethindrone was reached by Day 17 and steady-state with respect to ethinyl estradiol was reached by Day 13.
Mean SHBG concentrations were increased by 150% from baseline (57.5 nmol/L) to 144 nmol/L at steady-state.Figure 1. Mean (± Standard Deviation) Plasma Norethindrone Concentration-Time Profile Following Single-Dose Oral Administration of NA/EE and Fe Tablets (chewed and swallowed) to Healthy Female Volunteers under Fasting Conditions (n = 35)Figure 2. Mean (± Standard Deviation) Plasma Ethinyl Estradiol Concentration-Time Profile Following Single-Dose Oral Administration of NA/EE and Fe Tablets (chewed and swallowed) to Healthy Female Volunteers under Fasting Conditions (n = 35)
Table 1. Summary of Norethindrone (NE) and Ethinyl Estradiol (EE) Pharmacokinetics Following Single-Dose Oral Administration of NA/EE and Fe Tablets (chewed and swallowed) to Healthy Female Volunteers Under Fasting Conditions (n = 35)
The harmonic mean (0.693/mean terminal phase rate constant) is reported for t½, and the median (range) is reported for tmax (% CV) by Pharmacokinetic Parameter
Cmax = Maximum plasma concentration
tmax = Time of Cmax
AUC(0-tldc) = Area under plasma concentration versus time curve from 0 to tldc, the time of last determinable concentration
AUC(0-inf) = Area under the plasma concentration versus time curve from time 0 to infinity
t½ = Terminal phase half-life
% CV = Coefficient of Variation (%)
NA/EE and Fe tablets may be administered without regard to meals.
A single-dose administration of norethindrone acetate/ethinyl estradiol tablets with food decreased the maximum concentration of norethindrone by 51% and increased the extent of absorption by 15% and decreased the maximum concentration of ethinyl estradiol by 51% but not the extent of absorption.
Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (greater than 95%); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.
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.
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.
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/ethinyl estradiol tablets are approximately 8 hours and 14 hours, respectively.
13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
[See Warnings and Precautions (5.2, 5.10) and Use in Specific Populations (8.1).]
14 Clinical Studies
The data presented in Section 14 are from a clinical trial conducted with a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets. NA/EE and Fe is bioequivalent to these norethindrone acetate/ethinyl estradiol tablets.
In a clinical study, 743 women 18 to 45 years of age were studied to assess the efficacy of norethindrone acetate/ethinyl estradiol tablets, for up to six 28-day cycles providing a total of 3,823 treatment-cycles of exposure. The racial demographic of all enrolled women was: 70% Caucasian, 16% African-American, 10% Hispanic, 2% Asian and 2% Other. Women with body mass index (BMI) greater than 35 kg/m2 were excluded from the study. The weight range for those women treated was 90 to 260 pounds, with a mean weight of 147 pounds. Among the women in the study, about 40% had not used hormonal contraception immediately prior to enrolling in this study.
A total of 583 women completed 6 cycles of treatment. There were a total of 5 on-treatment pregnancies in 3,565 treatment cycles during which no backup contraception was used. The Pearl Index for norethindrone acetate and ethinyl estradiol tablets was 1.82 (95% confidence interval 0.59 - 4.25).
16.1 How Supplied
NA/EE and Fe is available in blister cards (dispensers) containing 28 tablets:
16.2 Storage Conditions
Store at 20 - 25° C (68 - 77° F); excursions permitted to 15 - 30° C (59 - 86° F) [see USP Controlled Room Temperature].
Keep this drug and all drugs out of the reach of children.
17 Patient Counseling Information
See FDA-approved patient labeling (Patient Information)
Counsel patients on the following information:
- •Cigarette smoking increases the risk of serious cardiovascular events from COC use, and women who are over 35 years old and smoke should not use COCs.
- •NA/EE and Fe tablets do not protect against HIV infection (AIDS) and other sexually transmitted infections.
- •The Warnings and Precautions associated with COCs.
- •NA/EE and Fe tablets is not to be used during pregnancy; if pregnancy occurs during use of NA/EE and Fe tablets, instruct the patient to stop further intake.
- •Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event tablets are missed. See “What to Do if You Miss Tablets” section in FDA-approved patient labeling.
- •Use a back-up or alternative method of contraception when enzyme inducers are used with NA/EE and Fe tablets.
- •COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established.
- •Women who start COCs postpartum, and who have not yet had a period, should use an additional method of contraception until they have taken a white tablet for 7 consecutive days.
- •Amenorrhea may occur. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles.
Spl Patient Package Insert
FDA-Approved Patient Labeling
Guide for Using Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets
WARNING TO WOMEN WHO SMOKE
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.
Birth control pills help to lower the chances of becoming pregnant when taken as directed. They do not protect against HIV infection (AIDS) and other sexually transmitted infections.
What is NA/EE and Fe tablets?
NA/EE and Fe tablets is a birth control pill. It contains two female hormones, an estrogen called ethinyl estradiol, and a progestin called norethindrone acetate.
How well does NA/EE and Fe tablets work?
Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The better you follow the directions, the less chance you have of getting pregnant.
Based on the results of one clinical study of a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets lasting six months, about 1 to 4 out of 100 women may get pregnant during the first year they use NA/EE and Fe tablets.
Women with a BMI above 35 kg/m2 were not studied in the clinical trial, so it is not known how well NA/EE and Fe tablets protects against pregnancy in such women. If you are overweight, discuss with your healthcare provider whether NA/EE and Fe is the best choice for you.
The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.
How do I take NA/EE and Fe tablets?
Norethindrone Acetate And Ethinyl Estradiol Chewable Tablets (1 Mg/20 Mcg) And Ferrous Fumarate Chewable Tablets, 5 Pouches, Each Containing 1 Blister Card; 28 Tablets Each, Carton Text
and Ethinyl Estradiol Tablets
and Ferrous Fumarate Tablets
CHEWABLE FRESH MINT FAVOR
This carton contains 5 pouches.
Each pouch contains 1 blister
card of 28 tablets.
Norethindrone Acetate and
Ethinyl Estradiol Tablets and
Ferrous Fumarate Tablets 1mg/20mcg
provide 24 days of active therapy.
*Ferrous fumarate tablets are not USP
for dissolution and assay.
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 review the disclaimer below.