The efficacy of Microgestin 24 Fe in women with a body mass index (BMI) of > 35 kg/m2 has not been evaluated.

2.1 How to Start Microgestin 24 Fe

2.2 How to Take Microgestin 24 Fe

First-trimester

• After a first-trimester abortion or miscarriage, Microgestin 24 Fe may be started immediately. An additional method of contraception is not needed if Microgestin 24 Fe is started immediately.
• If Microgestin 24 Fe is 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 Microgestin 24 Fe.

• Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Microgestin 24 Fe 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 Microgestin 24 Fe[see Contraindications (4), Warnings and Precautions (5.1), and FDA-approved Patient Labeling].

• Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Microgestin 24 Fe 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 Microgestin 24 Fe[see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1 and 8.3)].

2.3 Missed Tablets

2.4 Advice in Case of Gastrointestinal Disturbances

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

• 24 pale yellow, round (active) tablets debossed with "L2" on one side and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.
• 4 brown, round (non-hormonal placebo) tablets debossed with "F" on one side and "N " on the other side and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.

• 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 inherited or acquired hypercoagulopathies[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 uncontrolled hypertension[see Warnings and Precautions (5.4)]
  • Have diabetes mellitus with vascular disease[see Warnings and Precautions (5.6)]
  • Have headaches with focal neurological symptoms or have migraine headaches with aura[see Warnings and Precautions (5.7)]
    • Women over age 35 with any migraine headaches [see Warnings and Precautions (5.7)]
• Liver tumors, benign or malignant, or liver disease[see Warnings and Precautions (5.2)]
• Undiagnosed abnormal uterine bleeding[see Warnings and Precautions (5.8)]
• Pregnancy, because there is no reason to use COCs during pregnancy[ see Warnings and Precautions (5.9)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 (5.11)]
• Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations[see Warnings and Precautions (5.3)]

5.1 Thrombotic Disorders and Other Vascular Problems

• Stop Microgestin 24 Fe if an arterial thrombotic event or venous thromboembolic (VTE) event occurs.
• Stop Microgestin 24 Fe 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 Microgestin 24 Fe 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 Microgestin 24 Fe 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

Do not use Microgestin 24 Fe 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 Microgestin 24 Fe if jaundice develops.

Liver Tumors

Microgestin 24 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 (>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

5.4 High Blood Pressure

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

5.6 Carbohydrate and Lipid Metabolic Effects

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

Consider discontinuation of Microgestin 24 Fe 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 (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, 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, at least in part, due to bleeding or spotting. Based on data from the clinical trial, [24-38%] of women using norethindrone acetate and ethinyl estradiol 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 Microgestin 24 Fe may experience absence of withdrawal bleeding, even if they are not pregnant. In the clinical trial with norethindrone acetate and ethinyl estradiol tablets, 31 to 41% of the women using norethindrone acetate and ethinyl estradiol 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

Discontinue Microgestin 24 Fe 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

5.11 Carcinoma of the Breast and Cervix

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.

5.12 Effect on Binding Globulins

5.13 Monitoring

5.14 Hereditary Angioedema

5.15 Chloasma

• Serious cardiovascular events and stroke[see Boxed Warning and Warnings and Precautions (5.1)]
• Vascular events[see Warnings and Precautions (5.1)]
• Liver disease[see Warnings and Precautions (5.2)]

• Irregular uterine bleeding
• Nausea
• Breast tenderness
• Headache

6.1 Clinical Trial Experience

The safety of norethindrone acetate and ethinyl estradiol 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 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 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, 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 Postmarketing Experience

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

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 20-25%. 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/ritnoavir, 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 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

7.4 Interactions with Laboratory Tests

8.1 Pregnancy

Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion.

Women who do not breastfeed should not start COCs earlier than 4 weeks postpartum.

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

8.8 Body Mass Index

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

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 Microgestin 24 Fe 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 in 17 healthy female volunteers are provided in Figures 1 and 2, and Table 1.

Following multiple-dose administration of norethindrone acetate and ethinyl estradiol 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.

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.

A single-dose administration of Microgestin 24 Fe tablet 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 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 are approximately 8 hours and 14 hours, respectively.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

Carton of 1 NDC 51862-648-02

Carton of 3 NDC 51862-648-03

Carton of 6 NDC 51862-648-06

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

• 24 pale yellow, round (active) tablets debossed with "L2" on one side and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.
• 4 brown, round (non-hormonal placebo) tablets debossed with "F" on one side and "N " on the other side and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.

16.2 Storage Conditions

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