Norethindrone Acetate, Ethinyl Estradiol And Ferrous Fumarate

Description

11 DESCRIPTION Mibelas 24 Fe provides an oral contraceptive regimen consisting of 24 white to off white active chewable tablets that contain the active ingredients, followed by 4 brown mottled non-hormonal placebo tablets as specified below: 24 white to off white, round flat face beveled edged tablets debossed with "LU" on one side and "N81" on the other side each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. 4 brown mottled, round flat face beveled edged tablets debossed with "LU" on one side and "M22" on the other side each containing 75 mg ferrous fumarate Each white to off white active chewable tablet also contains the following inactive ingredients: acacia, confectioner's sugar, corn starch, lactose monohydrate, magnesium stearate and talc. Each brown mottled placebo tablet contains ferrous fumarate, magnesium stereate, microcrystalline cellulose, povidone, sodium starch glycolate, and sucrose. The ferrous fumarate tablets do not serve any therapeutic purpose. The empirical formula of ethinyl estradiol is C 20 H 24 O 2 and the structural formula is: Ethinyl Estradiol The chemical name of ethinyl estradiol is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-]. The molecular weight of ethinyl estradiol is 296.40. The empirical formula of norethindrone acetate is C 22 H 28 O 3 and the structural formula is: Norethindrone Acetate USP 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. Ethinyl Estradiol Norethindrone Acetate

What Is Norethindrone Acetate, Ethinyl Estradiol And Ferrous Fumarate Used For?

1 INDICATIONS AND USAGE Mibelas 24 Fe is an estrogen/progestin COC indicated for use by women to prevent pregnancy ( 1 ) The efficacy in women with a body mass index of more than 35 kg/m 2 has not been evaluated ( 1 , 8.8 ) Mibelas™ 24 Fe is indicated for use by females of reproductive age to prevent pregnancy [see CLINICAL STUDIES ( 14 )]. The efficacy of Mibelas 24 Fe in women with a body mass index (BMI) of more than 35 kg/m 2 has not been evaluated.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION One tablet daily chewed and swallowed or swallowed whole taken at the same time of day. Follow with 8 ounces of water ( 2.1 ) Take one tablet by mouth at the same time every day for 28 days ( 2.1 ) Take tablets in the order directed on the blister pack ( 2.1 ) Tablets may be administered without regard to meals ( 12.3 ) 2.1 How to Take Mibelas 24 Fe To achieve maximum contraceptive effectiveness, Mibelas 24 Fe must be taken exactly as directed. Instruct patients to take one tablet by mouth at the same time every day. The tablet may be chewed and swallowed or swallowed whole. The patient should drink a full glass (8 ounces) of water immediately after the white tablets are chewed or swallowed whole. Tablets must be taken in the order directed on the blister pack. Tablets should not be skipped or taken at intervals exceeding 24 hours. For patient instructions for missed tablets, [see FDA-approved patient labeling]. Mibelas 24 Fe may be administered without regard to meals [see CLINICAL PHARMACOLOGY ( 12.3 )]. 2.2 How to Start Mibelas 24 Fe Instruct the patient to begin taking Mibelas 24 Fe either on the first day of her menstrual period (Day 1 Start) or on the first Sunday after the onset of her menstrual period (Sunday Start). Day 1 Start During the first cycle of Mibelas 24 Fe use, instruct the patient to take one white Mibelas 24 Fe tablet daily, beginning on Day one (1) of her menstrual cycle (the first day of menstruation is Day one). She should take one white Mibelas 24 Fe tablet daily for 24 consecutive days, followed by one brown tablet daily on days 25 through 28. Mibelas 24 Fe should be taken in the order directed on the package at the same time each day. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days if she starts taking Mibelas 24 Fe on a day other than the first day of her menstrual cycle. The possibility of ovulation and conception prior to initiation of medication should be considered. Sunday Start During the first cycle of Mibelas 24 Fe use, instruct the patient to take one white Mibelas 24 Fe tablet daily, beginning on the first Sunday after the onset of her menstrual period. She should take one white Mibelas 24 Fe tablet daily for 24 consecutive days, followed by one brown tablet daily on days 25 through 28. Mibelas 24 Fe should be taken in the order directed on the package at the same time each day. Mibelas 24 Fe should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. The patient should begin her next and all subsequent 28-day regimens of Mibelas 24 Fe on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her white Mibelas 24 Fe tablets on the...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The most common adverse reactions in clinical trials (greater than or equal to 2%) were: headache, vaginal candidiasis, nausea, menstrual cramps, breast tenderness, bacterial vaginitis, abnormal cervical smear, acne, mood swings, and weight gain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data presented in Section 6.1 are from a clinical trial conducted with a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets. Mibelas 24 Fe is bioequivalent to these norethindrone acetate/ethinyl estradiol tablets. Common Adverse Reactions (Greater Than or Equal to 2% of all Treated Subjects) The most common adverse reactions reported by at least 2% of the 743 women using norethindrone acetate/ethinyl estradiol tablets were the following, in order of decreasing incidence: headache (6.3%), vaginal candidiasis (6.1%), nausea (4.6%), menstrual cramps (4.4%), breast tenderness (3.4%), bacterial vaginitis (3.1%), abnormal cervical smear (3.1%), acne (2.7%), mood swings (2.2%), and weight gain (2.0%). Adverse Reactions Leading to Study Discontinuation Among the 743 women using norethindrone acetate/ethinyl estradiol tablets, 46 women (6.2%) withdrew because of an adverse event. Adverse events occurring in 3 or more subjects leading to discontinuation of treatment were, in decreasing order: abnormal or irregular bleeding (1.3%), nausea (0.8%), menstrual cramps (0.5%), and increased blood pressure (0.4%). 6.2 Postmarketing Experience 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 - 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 - 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 8-10 years of COC use. Figure 1 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 neverused COCs. The following adverse reactions have been identified during post approval use of a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Adverse reactions are grouped into System Organ Classes. Vascular Disorders Thrombosis/embolism (coronary artery, pulmonary, cerebral, deep vein). Hepatobiliary Disorders Cholelithiasis, cholecystitis, hepatic adenoma, hemangioma of liver. Immune System Disorders Hypersensitivity reaction. Skin and Subcutaneous Disorders Alopecia, rash...

Drug Interactions

7 DRUG INTERACTIONS Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with COCs ( 7.1 ) 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 Mibelas 24 Fe. 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...

Contraindications

4 CONTRAINDICATIONS A high risk of arterial or venous thrombotic diseases ( 4 ) Breast cancer Liver tumors or liver disease ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Pregnancy ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 ) Mibelas 24 Fe is contraindicated in females who are known to have or develop the following conditions:

Pregnancy and Breastfeeding

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. The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion.

8.3 Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk

Overdosage

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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Mibelas 24 Fe is available in carton (NDC 68180-911-73) containing three pouches, each pouch containing a blister of 28 tablets (NDC 68180-911-71). Each blister contains 28 tablets in the following order: 24 white to off white, round, flat face beveled edged (active) chewable tablets debossed with "LU" on one side and "N81" on the other side, and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. 4 brown mottled, round, flat face beveled edged (non-hormonal placebo) tablets debossed with "LU" on one side and "M22" 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 25° C (77° F); excursions permitted to 15 to 30° C (59 to 86° F) [see USP Controlled Room Temperature]. Keep this drug and all drugs out of the reach of children.