Norethindrone, Ethinyl Estradiol and Ferrous Fumarate

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are indicated for use by females of reproductive age to prevent pregnancy [see Clinical Studies (14)].

The efficacy of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets in women with a body mass index (BMI) of more than 35 kg/m2 has not been evaluated.

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets are available in blister packs.

Each blister pack contains 28 tablets in the following order:

• 24 white, round, (active) chewable tablets debossed with “AN” on one side and “30” on the other side, and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.
• 4 brown, round (non-hormonal placebo) tablets debossed with “AN” on one side and “364” on the other side, and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.

5.1 Thromboembolic Disorders and Other Vascular Problems

Stop norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets if an arterial or deep venous thrombotic event (VTE) 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.

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.

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 per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COC. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued.

Use of COCs also increases the risk of arterial thrombosis such as strokes and myocardial infarctions, especially in women with other risk factors for these events. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest in older (greater than 35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with underlying risk factors.

Use COCs with caution in women with cardiovascular disease risk factors.

5.2 Liver Disease

Impaired Liver Function

Do not use norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets in women with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4)]. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Discontinue 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 (greater than 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.

5.3 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

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 also worsen existing gallbladder disease.

A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.

5.6       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 in a dose-related fashion.

Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of women will have adverse lipid changes while on COCs.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

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) [see Contraindications (4)].

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 COC.

Based on patient diaries from a clinical trial evaluating the safety and efficacy of a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets, 24% to 35% of women experienced unscheduled bleeding per cycle. A total of 10 subjects out of 743 (1.3%) discontinued due to bleeding or spotting.

Amenorrhea and Oligomenorrhea

Women who are not pregnant and use norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may experience amenorrhea. In the clinical trial with a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets and ferrous fumarate tablets, 22% to 36% of the women using norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets and ferrous fumarate tablets experienced amenorrhea in at least one of 6 cycles of use. Some women may experience post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent.

If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.

5.9       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 if pregnancy is confirmed.

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

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  Carcinoma of the Breasts and Cervix

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)].

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

The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormones or cortisol therapy may need to be increased.

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.

Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.

No drug-drug interaction studies were conducted with norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets.

7.1 Effects of Other Drugs on Combined Oral Contraceptives

Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate and products containing St. John’s wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone concentrations.

Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma concentrations of the estrogen and progestin have been noted in some cases of co-administration of HIV/HCV protease inhibitors or of non-nucleoside reverse transcriptase inhibitors.

Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.

7.2 Effects of Combined Oral Contraceptives on Other Drugs

COCs containing ethinyl estradiol may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

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

7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Do not co-administer norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.3)].

7.4       Interference with Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets provide an oral contraceptive regimen consisting of 24 white active chewable tablets that contain the active ingredients, followed by 4 brown non-hormonal placebo tablets as specified below:

• 24 white, round tablets each containing 1 mg norethindrone acetate, USP and 20 mcg ethinyl estradiol, USP.
• 4 brown, round tablets each containing 75 mg ferrous fumarate.

Each white active chewable tablet also contains the following inactive ingredients: acacia, confectioner’s sugar, lactose monohydrate, magnesium stearate, microcrystalline cellulose and talc.

Each brown placebo tablet contains ferrous fumarate, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, povidone, spearmint flavor and sucralose. The ferrous fumarate tablets do not serve any therapeutic purpose.

The empirical formula of ethinyl estradiol, USP is C20H24O2 and the structural formula is:

The chemical name of ethinyl estradiol is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-]. The molecular weight of ethinyl estradiol is 296.40.

The empirical formula of norethindrone acetate, USP is C22H28O3 and the structural formula is:

The chemical name of norethindrone acetate is [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-]. The molecular weight of norethindrone acetate is 340.46.

In the U.S.

• Lo Loestrin Fe
• Lo Minastrin Fe

Available Dosage Forms:

• Tablet
• Tablet, Chewable

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For norethindrone, ethinyl estradiol, and ferrous fumarate, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to norethindrone, ethinyl estradiol, and ferrous fumarate or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies on the relationship of age to the effects of norethindrone, ethinyl estradiol, and ferrous fumarate combination have not been performed in the pediatric population. However, pediatric-specific problems that would limit the usefulness of norethindrone, ethinyl estradiol, and ferrous fumarate in teenagers are not expected. norethindrone, ethinyl estradiol, and ferrous fumarate may be used for birth control in teenage females but should not be used before the start of menstruation.

Geriatric

Appropriate studies on the relationship of age to the effects of norethindrone, ethinyl estradiol, and ferrous fumarate combination have not been performed in the geriatric population. norethindrone, ethinyl estradiol, and ferrous fumarate should not be used in elderly women.

Pregnancy

Breast Feeding

Studies suggest that this medication may alter milk production or composition. If an alternative to this medication is not prescribed, you should monitor the infant for side effects and adequate milk intake.

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking norethindrone, ethinyl estradiol, and ferrous fumarate, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using norethindrone, ethinyl estradiol, and ferrous fumarate with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Dasabuvir
• Ombitasvir
• Paritaprevir
• Ritonavir
• Tranexamic Acid

Using norethindrone, ethinyl estradiol, and ferrous fumarate with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Anagrelide
• Aprepitant
• Boceprevir
• Bosentan
• Bupropion
• Carbamazepine
• Ceritinib
• Dabrafenib
• Darunavir
• Dexamethasone
• Dimercaprol
• Donepezil
• Eliglustat
• Eltrombopag
• Enzalutamide
• Fosphenytoin
• Griseofulvin
• Idelalisib
• Isotretinoin
• Lesinurad
• Lixisenatide
• Lumacaftor
• Mitotane
• Modafinil
• Oxcarbazepine
• Paclitaxel
• Paclitaxel Protein-Bound
• Phenytoin
• Piperaquine
• Pitolisant
• Prednisone
• Rifabutin
• Rifampin
• St John's Wort
• Sugammadex
• Theophylline
• Tizanidine
• Topiramate
• Ulipristal
• Valproic Acid

Using norethindrone, ethinyl estradiol, and ferrous fumarate with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alprazolam
• Amprenavir
• Atazanavir
• Bacampicillin
• Betamethasone
• Bexarotene
• Carbidopa
• Cefdinir
• Clarithromycin
• Colesevelam
• Cyclosporine
• Delafloxacin
• Delavirdine
• Demeclocycline
• Dolutegravir
• Doxycycline
• Efavirenz
• Eslicarbazepine Acetate
• Etoricoxib
• Fosamprenavir
• Fosaprepitant
• Gatifloxacin
• Ginseng
• Grepafloxacin
• Lamotrigine
• Levodopa
• Levofloxacin
• Levothyroxine
• Licorice
• Lomefloxacin
• Methyldopa
• Minocycline
• Moxifloxacin
• Mycophenolate Mofetil
• Mycophenolic Acid
• Nelfinavir
• Norfloxacin
• Ofloxacin
• Omeprazole
• Parecoxib
• Penicillamine
• Prednisolone
• Rifapentine
• Ritonavir
• Roflumilast
• Rosuvastatin
• Rufinamide
• Selegiline
• Telaprevir
• Temafloxacin
• Tetracycline
• Tipranavir
• Troglitazone
• Troleandomycin
• Trovafloxacin Mesylate
• Valdecoxib
• Voriconazole
• Warfarin
• Zinc

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using norethindrone, ethinyl estradiol, and ferrous fumarate with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use norethindrone, ethinyl estradiol, and ferrous fumarate, or give you special instructions about the use of food, alcohol, or tobacco.

• Caffeine
• Dairy Food
• Grapefruit Juice
• Phytic Acid Containing Food

Other Medical Problems

The presence of other medical problems may affect the use of norethindrone, ethinyl estradiol, and ferrous fumarate. Make sure you tell your doctor if you have any other medical problems, especially:

• Abnormal or unusual vaginal bleeding or
• Blood clots (eg, deep vein thrombosis, pulmonary embolism), or history of or
• Breast cancer, active or history of or
• Diabetes with kidney, eye, nerve, or blood vessel damage or
• Heart attack, history of or
• Heart or blood vessel disease (eg, coronary artery disease, heart valve problems) or
• Heart rhythm problems (atrial fibrillation) or
• Hypertension (high blood pressure), poorly controlled or
• Liver disease, including tumors or cancer or
• Migraine headache, new or worse or a new kind of headache or
• Problems with circulation or blood clots, now or in the past or
• Stroke, history of—Should not be used in patients with these conditions.

• Angioedema (swelling of the face, tongue, or throat), inherited or
• Cervical cancer or intraepithelial neoplasia or
• Chloasma gravidarum (skin disorder during pregnancy), history of or
• Cholestasis (bile problem) during pregnancy, history of or
• Depression, history of or
• Diabetes or
• Dyslipidemia (high cholesterol or fats in the blood), uncontrolled or
• Gallbladder disease or
• Hypertension (high blood pressure)—Use with caution. May make these conditions worse.