2.1 How to Start Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are dispensed in a blister card [see How Supplied/Storage and Handling (16)]. Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may be started using either a Day 1 start or a Sunday start (see Table 1). For the first cycle of a Sunday Start regimen, an additional method of contraception must be used until after the first 7 consecutive days of administration.

2.2 How to Take Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets

Table 1: Instructions for Administration of Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets

Starting Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets after Abortion or Miscarriage

First-trimester

• After a first-trimester abortion or miscarriage, norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may be started immediately. An additional method of contraception is not needed if norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are started immediately.
• If norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are not started within 5 days after termination of the pregnancy, the patient must use additional non-hormonal contraception (such as condoms and spermicide) for the first 7 days of her first 28-day course of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets.

Second-trimester

• Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets following the instructions in Table 1 for Sunday start. Use additional non-hormonal contraception (such as condoms and spermicide) for the first 7 days of the patient’s first 28-day course of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets [see Contraindications (4), and Warnings and Precautions (5.1)].

Starting Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets after Childbirth

• Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets following the instructions in Table 1 for women not currently using hormonal contraception.
• If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1 and 8.2)].

2.3 Missed Tablets

Table 2: Instructions for Missed Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets

2.4 Advice in Case of Gastrointestinal Disturbances

In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures must be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking a white tablet, handle this as a missed tablet [see Dosage and Administration (2.3)].

5.1 Thrombotic Disorders and Other Vascular Problems

• Stop norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if an arterial thrombotic event or venous thromboembolic (VTE) event occurs.
• Stop norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately [see Adverse Reactions (6.2)].
• If feasible, stop norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during the following prolonged immobilization.
• Start norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate 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 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COCs and when restarting oral contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs 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). This risk increases with age, particularly in women over 35 years of age who smoke.
• Use COCs with caution in women with cardiovascular disease risk factors.

5.2 Liver Disease

Impaired Liver Function

Do not use norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if jaundice develops.

Liver Tumors

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are 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 (>8 years) COC users. However, the risk of liver cancers in COC users is less than one case per million users.

5.3 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 (4)]. Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.4 High Blood Pressure

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate 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.

5.5 Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may 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.

5.6 Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who are taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. COCs may decrease glucose tolerance.

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.

5.7 Headache

If a woman taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if indicated.

Consider discontinuation of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

5.8 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 contraceptive product.

In a clinical trial of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, the frequency and duration of unscheduled bleeding and/or spotting was assessed in 743 women (3,823 28-day cycles). A total of 10 subjects (1.3%) discontinued norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, at least in part, due to bleeding or spotting. Based on data from the clinical trial, [24% to 38%] of women using norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets experienced unscheduled bleeding per cycle in the six months of the trial. The percent of women who experienced unscheduled bleeding tended to decrease over time.

Amenorrhea and Oligomenorrhea

Women who use norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may experience absence of withdrawal bleeding, even if they are not pregnant. In the clinical trial with norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, 31% to 41% of the women using norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets did not have a withdrawal menses in at least one of 6 cycles of use.

Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs, 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.

5.9 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets use if pregnancy is confirmed.

Administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].

5.10 Depression

Carefully observe women with a history of depression and discontinue norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if depression recurs to a serious degree.

5.11 Malignant Neoplasms

Breast Cancer

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].

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 (6.2)].

Cervical Cancer

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.

5.12 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 hormone or cortisol therapy may need to be increased.

5.13 Monitoring

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.

5.14 Hereditary Angioedema

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

5.15 Chloasma

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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets.

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 safety of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets was evaluated in 743 subjects who participated in an open-label, randomized, active-controlled, multicenter clinical trial of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets for contraception. This trial examined healthy, non-pregnant volunteers aged 18 to 45 years, who were sexually active and had a body mass index of ≤ 35 kg/m2. Subjects were followed for up to six 28-day cycles providing a total of 3,823 treatment-cycles of exposure.

Common Adverse Reactions (≥ 2% of all subjects): The most common adverse reactions reported by at least 2% of the 743 women using norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate 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%), mood changes (including mood swings (2.2%) and depression (1.1%), bacterial vaginitis (3.1%), acne (2.7%), and weight gain (2.0%).

Adverse Reactions Leading to Study Discontinuation: Among the 743 women using norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate 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 bleeding (0.9%), nausea (0.8%), mood changes (0.8%), menstrual cramps (0.4%), increased blood pressure (0.4%), and irregular bleeding (0.4%).

6.2 Post-marketing Experience

Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (Figure 1).

Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 to 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8 to 10 years of COC use.

Figure 1: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives

RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs.

The following adverse reactions have been identified during post approval use of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Cardiovascular: chest pain, palpitations, tachycardia, angina pectoris, myocardial infarction.

Endocrine disorders: hypothyroidism, hyperthyroidism.

Eye disorders: blurred vision, visual impairment, transient blindness, corneal thinning, change in corneal curvature (steepening).

GI disorders: nausea, vomiting, abdominal pain, constipation, pancreatitis.

Hepatobiliary disorders: cholelithiasis, cholecystitis, hepatic adenoma, hemangioma of liver.

Immune system disorders: anaphylactic reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms.

Infections: vaginal infection.

Metabolism and nutrition disorders: change in weight or appetite (increase or decrease). hypoglycemia, diabetes mellitus, anemia.

Musculoskeletal and connective tissue disorders: myalgia.

Skin and subcutaneous disorders: alopecia, rash (generalized and allergic), pruritus, skin discoloration, night sweats, swelling face or lips, hirsutism, skin burning sensation, erythema multiforme, erythema nodosum, hemorrhagic eruption.

Nervous system disorders: headache, dizziness, migraine, hyperesthesia, paraesthesia, hypoaesthesia, somnolence, loss of consciousness, sensory disturbance.

Psychiatric disorders: mood swings, depression, insomnia, anxiety, suicidal ideation, panic attack, changes in libido, bipolar disorder, dissociation, homicidal ideation.

Renal and urinary disorders: pollakiuria, dysuria, cystitis-like syndrome.

Reproductive system and breast disorders: breast changes (tenderness, pain, enlargement, and secretion), premenstrual syndrome, ovarian cyst, pelvic pain, ovarian cyst ruptured, pelvic fluid collection.

Vascular disorders: hot flush, thrombosis/embolism (coronary artery, pulmonary, cerebral, deep vein), migraine, transient ischemic attack, ischemic stroke.

7.1 Effects of Other Drugs on Combined Oral Contraceptives

Substances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs:

Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of oral contraceptives including phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between COCs 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 or rosuvastatin and certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20% to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, 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 estrogen and/or progestin have been noted in some cases of co-administration with HIV 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 or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).

7.2 Effects of Combined Oral Contraceptives on Other Drugs

COCs containing EE 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, and temazepam. 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 increases with use of COCs [see Warnings and Precautions (5.12)].

7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Co-administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations [see Warnings and Precautions (5.3)]. Co-administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets and glecaprevir/pibrentasvir is not recommended due to potential for ALT elevations.

7.4 Interactions 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.

8.1 Pregnancy

Risk Summary

There is no use for contraception in pregnancy; therefore, norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb reduction defects) following exposure to CHCs before conception or during early pregnancy.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively.

Data

Human Data

Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy.

8.2 Lactation

Risk Summary

Contraceptive hormones and/or metabolites are present in human milk. CHCs can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breastfeeding [see Dosage and Administration (2.2)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets and any potential adverse effects on the breastfed child from norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets or from the underlying maternal condition.

8.4 Pediatric Use

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

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets have not been studied in postmenopausal women and are not indicated in this population.

8.6 Hepatic Impairment

The pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate 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)].

8.7 Renal Impairment

The pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets has not been studied in women with renal impairment.

8.8 Body Mass Index

The safety and efficacy of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets in women with a body mass index (BMI) > 35 kg/m2 has not been evaluated [see Clinical Studies (14)].

12.1 Mechanism of Action

CHCs prevent pregnancy primarily by suppressing ovulation.

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted with norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets.

12.3 Pharmacokinetics

Absorption

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 rapidly absorbed from norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 4 hours postdose. 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- and multiple-dose administrations of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets in 17 healthy female volunteers are provided in Figures 2 and 3, and Table 3.

Following multiple-dose administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, 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 and ethinyl estradiol tablets and ferrous fumarate 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 2. Mean Plasma Norethindrone Concentration-Time Profiles Following Single- and Multiple-Dose Oral Administration of Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17)

Figure 3. Mean Plasma Ethinyl Estradiol Concentration-Time Profiles Following Single- and Multiple-Dose Oral Administration of Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17)

Table 3. Summary of Norethindrone (NE) and Ethinyl Estradiol (EE) Pharmacokinetics Following Single- and Multiple-Dose Oral Administration of Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17)

Cmax = Maximum plasma concentration

tmax = Time of Cmax

Cmin = minimum plasma concentration at steady-state

AUC(0 to 24) = Area under plasma concentration versus time curve from 0 to 24 hours

t1/2 = Apparent first-order terminal elimination half-life

Cavg = Average plasma concentration = AUC(0 to 24)/24

% CV = Coefficient of Variation (%)

SHBG = Sex Hormone Binding Globulin (nmol/L)

aThe harmonic mean (0.693/mean apparent elimination rate constant) is reported for t1/2, and the median (range) is reported for tmax

bThe SHBG concentration reported here is the pre-dose concentration.

Food Effect

A single-dose administration of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets with food decreased the maximum concentration of norethindrone by 11% and increased the extent of absorption by 27% and decreased the maximum concentration of ethinyl estradiol by 30% but not the extent of absorption.

Distribution

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 L/kg to 4 L/kg. Plasma protein binding of both steroids is extensive (>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.

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.

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 8 hours and 14 hours, respectively.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[See Warnings and Precautions (5.2, 5.11)]

16.1 How Supplied

Norethindrone acetate and ethinyl estradiol tablets USP, 1 mg/20 mcg and ferrous fumarate tablets, 75 mg are available in blister card dispensers containing 28 tablets:

Cartons of 3 blister cards (dispensers)            NDC 69238-1582-3

Each blister card (28 tablets) contains in the following order:

• 24 white, flat faced, beveled edge, round shaped (active) tablets debossed with “AL1” on one side and plain on the other side, each containing 1 mg norethindrone acetate, USP and 20 mcg ethinyl estradiol, USP.
• 4 natural color brown, flat faced, beveled edge, round (non-hormonal placebo) tablets debossed with “ AL2” on one side and plain on the other side, each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.

16.2 Storage Conditions

• Store at 20º to 25ºC (68º to 77º F); excursions permitted between 15º to 30ºC (59º to 86º F) [see USP Controlled Room Temperature].
• Protect from light.
• Keep this drug and all drugs out of the reach of children.