FDA Label for Hailey 24 Fe

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

Hailey 24 Fe is indicated for use by women to prevent pregnancy [see Clinical Studies (14)].

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

2 Dosage And Administration

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How To Start Hailey 24 Fe

Hailey 24 Fe is dispensed in a blister card [see How Supplied/Storage and Handling (16)]. Hailey 24 Fe 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.

How To Take Hailey 24 Fe

•  Table 1: Instructions for Administration of Hailey 24 Fe
Hailey 24 Fe active tablets are white (Day 1 to Day 24).
Hailey 24 Fe inactive tablets are brown (Day 25 to Day 28).Take first white active tablet without regard to meals on the first day of menses.
Take subsequent active tablets once daily at the same time each day for a total of 21 days.
Take one brown inactive tablet daily for 7 days and at the same time of day that active tablets were taken.
Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last inactive tablet).Take the white active tablet without regard to meals on the first Sunday after the onset of menses. Due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms and spermicide) for the first 7 days of the patient’s first cycle pack of Hailey 24 Fe.
Take subsequent active tablets once daily at the same time each day for a total of 24 days.
Take one brown tablet (ferrous fumarate) daily for the following 4 days and at the same time of day that active tablets were taken. A scheduled period should occur during the 4 days that the brown tablets are taken.
Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the Sunday after taking the last inactive tablet) and additional non-hormonal contraceptive is not needed.Transdermal patchOn the day when next application would have been scheduled.Vaginal ringOn the day when next insertion would have been scheduledInjectionOn the day when next injection would have been scheduledIntrauterine contraceptiveOn the day of removal
If the IUD is not removed on first day of the patient’s menstrual cycle, additional non-hormonal contraceptive (such as condoms and spermicide) is needed for the first seven days of the first cycle pack.ImplantOn the day of removal

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Starting COCs in women not currently using hormonal contraception (Day 1 Start or Sunday Start) Important: Consider the possibility of ovulation and conception prior to initiation of this product. Tablet Color:
	Day 1 Start:
Sunday Start: For each 28-day course, take in the following order:
Switching to Hailey 24 Fe from another oral contraceptive	Start on the same day that a new pack of the previous oral contraceptive would have started.
Switching from another contraceptive method to Hailey 24 Fe	Start Hailey 24 Fe:
Complete instructions on proper tablet usage are located in the FDA-approved patient labeling.

Starting Hailey 24 Fe after Abortion or Miscarriage

First-trimester

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

Second-trimester

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

Starting Hailey 24 Fe after Childbirth

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

Missed Tablets

•  Table 2: Instructions for Missed Hailey 24 Fe Tablets
If one active tablet is missed in Weeks 1, 2 or 3If two consecutive active tablets are missed in Week 1 or Week 2If two consecutive active tablets are missed in Week 3 or Week 4 or three or more consecutive active tablets are missed at any time

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Take the tablet as soon as possible. Take the next pill at the regular time, and continue taking one tablet a day until the pack is finished. Back-up contraception is not needed

Take the two missed tablets as soon as possible and the next two active tablets the next day. Continue taking one tablet a day until the pack is finished. Additional non-hormonal contraception (such as condoms and spermicide) must be used as back-up if the patient has sex within 7 days after missing tablets.

Day 1 Start: Throw out the rest of the pack and start a new pack that same day. Sunday Start: Continue taking one tablet a day until Sunday, then throw out the rest of the pack and start a new pack that same day. Additional non-hormonal contraception (such as condoms and spermicide) must be used as back-up if the patient has sex within 7 days after missing 3 tablets.

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 FDA-Approved Patient Labeling].

3 Dosage Forms And Strengths

Hailey™ 24 Fe (norethindrone acetate and ethinyl estradiol tablets USP and ferrous fumarate tablets) is available in blister packs.

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

• •24 white, round (active) tablets imprinted with ‘16’ on one side and ‘G’ on other side and each containing 1 mg norethindrone acetate, USP and 20 mcg ethinyl estradiol, USP.
• •4 brown, round (non-hormonal placebo) tablets imprinted with ‘17’ on one side and ‘G’ on other side and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.

4 Contraindications

Do not prescribe Hailey 24 Fe 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:
• oSmoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)]
• oHave deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)]
• oHave inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)]
• oHave cerebrovascular disease [see Warnings and Precautions (5.1)]
• oHave coronary artery disease [see Warnings and Precautions (5.1)]
• oHave 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)]
• oHave uncontrolled hypertension [see Warnings and Precautions (5.4)]
• oHave diabetes mellitus with vascular disease [see Warnings and Precautions (5.6)]
• oHave 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 Warnings And Precautions

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Thrombotic Disorders And Other Vascular Problems

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

Liver Disease

Impaired Liver Function

Do not use Hailey 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 Hailey 24 Fe if jaundice develops.

Liver Tumors

Hailey 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.

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 Hailey 24 Fe prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. Hailey 24 Fe can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

High Blood Pressure

Hailey 24 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 Hailey 24 Fe 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.

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.

Carbohydrate And Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who are taking Hailey 24 Fe. 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.

Headache

If a woman taking Hailey 24 Fe develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Hailey 24 Fe if indicated. Consider discontinuation of Hailey 24 Fe in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

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.

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 Hailey 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)].

Depression

Carefully observe women with a history of depression and discontinue Hailey 24 Fe if depression recurs to a serious degree.

Carcinoma Of The Breast And Cervix

Hailey 24 Fe is contraindicated in women who currently have or have had breast cancer because breast cancer is a 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.

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.

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.

Hereditary Angioedema

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

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 Hailey 24 Fe.

6 Adverse Reactions

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:

• •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)]

Adverse reactions commonly reported by COC users are:

• •Irregular uterine bleeding
• •Nausea
• •Breast tenderness
• •Headache

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 were 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%).

Postmarketing Experience

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 Drug Interactions

Consult the labeling of concurrently used drugs to obtain further information about interactions with oral contraceptives or the potential for enzyme alterations.

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/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]).

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)].

Concomitant Use With Hcv Combination Therapy – Liver Enzyme Elevation

Do not co-administer Hailey 24 Fe with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.3)].

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 Use In Specific Populations

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8.1 Pregnancy

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.

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

Advise the nursing mother to use another contraceptive method, when possible, 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 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 is not indicated in this population.

Hepatic Impairment

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

Renal Impairment

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

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)].

10 Overdosage

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.

11 Description

Hailey™ 24 Fe (norethindrone acetate and ethinyl estradiol tablets USP and ferrous fumarate tablets) is a combination oral contraceptive for oral administration consisting of active tablets containing norethindrone acetate, USP, a progestin, and ethinyl estradiol, USP, an estrogen, and placebo tablets containing ferrous fumarate, which serve no therapeutic purpose.

• •Each active white tablet contains 1 mg norethindrone acetate, USP and 20 mcg ethinyl estradiol, USP. Inactive ingredients include acacia, corn starch, lactose monohydrate, magnesium stearate, sucrose and talc.
• •Each placebo brown tablet contains 75 mg ferrous fumarate, microcrystalline cellulose, magnesium stearate, povidone, sodium starch glycolate, corn starch and talc. The ferrous fumarate tablets do not serve any therapeutic purpose.

The chemical name of ethinyl estradiol, USP is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-]. The empirical formula of ethinyl estradiol, USP is C20H24O2 and the structural formula is:

Structure 1.jpg - image 01

The chemical name of norethindrone acetate, USP is [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-]. The empirical formula of norethindrone acetate, USP is C22H28O3 and the structural formula is:

12 Clinical Pharmacology

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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.

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 1 and 2, 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 1. 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 1.jpg - image 03

Figure 2. 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)

C_max = Maximum plasma concentration

t_max = Time of C_max

C_min = minimum plasma concentration at steady-state

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

t_½ = Apparent first-order terminal elimination half-life

C_avg = Average plasma concentration = AUC_(0–24)/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 t_½, and the median (range) is reported for t_max.

^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 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 and ferrous fumarate tablets are approximately 8 hours and 14 hours, respectively.

13 Nonclinical Toxicology

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13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

[See Warnings and Precautions (5.2, 5.11) and Use in Specific Populations (8.1).]

14 Clinical Studies

In an active-controlled clinical trial, 743 women 18 to 45 years of age were studied to assess the efficacy of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, for up to six 28-day cycles. The racial demographic of women randomized to norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets was: 69.5% Caucasian, 15.5% African-American, 10.4% Hispanic, 2.3% Asian and 2.3% Native American/Other. Women with body mass index (BMI) greater than 35 mg/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 randomized to norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets, 38.9% 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 among women aged 18 to 45 years in 3,565 treatment cycles during which no back-up contraception was used. The Pearl Index for norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets was 1.82 (95% confidence interval 0.59 to 4.25).

16 How Supplied/Storage And Handling

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How Supplied

HaileyTM 24 Fe (norethindrone acetate and ethinyl estradiol tablets USP and ferrous fumarate tablets) is available in blister card dispensers containing 28 tablets:

NDC 68462-731-29 Cartons of 3 blister cards of 28 tablets.

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

• •24 white, round (active) tablets imprinted with ‘16’ on one side and ‘G’ on other side and each containing 1 mg norethindrone acetate, USP and 20 mcg ethinyl estradiol, USP.
• •4 brown, round (non-hormonal placebo) tablets imprinted with ‘17’ on one side and ‘G’ on other side and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.

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.

17 Patient Counseling Information

See FDA-approved Patient Labeling (Patient Information and Instructions for Use).

Counsel patients about the following information:

• •Cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs [see Boxed Warning].
• •Increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC [see Warnings and Precautions (5.1)].
• •Hailey 24 Fe does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
• •Hailey 24 Fe is not to be used during pregnancy; if pregnancy occurs during use of Hailey 24 Fe instruct the patient to stop further use [see Warnings and Precautions (5.9)].
• •Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed [see Dosage and Administration (2.2)].
• •Use a back-up or alternative method of contraception when enzyme inducers are used with Hailey 24 Fe [see Drug Interactions (7.1)].
• •COCs may reduce breast milk production; this is less likely to occur if breastfeeding is well established [see Use in Specific Populations (8.3)].
• •Women who start COCs postpartum, and who has not yet had a period, must use an additional method of contraception until she has taken a white tablet for 7 consecutive days [see Dosage and Administration (2.2)].
• •Amenorrhea may occur. Consider pregnancy in the event of amenorrhea at the time of the first missed period. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles [see Warnings and Precautions (5.8)].