Junel Fe 24

Ethinyl estradiol and norethindrone is a combination drug that contains female hormones that prevent ovulation (the release of an egg from an ovary). This medication also causes changes in your cervical mucus and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus.

Ethinyl estradiol and norethindrone is used as contraception to prevent pregnancy.

Ethinyl estradiol and norethindrone may also be used for purposes not listed in this medication guide.

Do not use birth control pills if you are pregnant or if you have recently had a baby.

You should not take birth control pills if you have any of the following conditions: uncontrolled high blood pressure, heart disease, a blood-clotting disorder, circulation problems, diabetic problems with your eyes or kidneys, unusual vaginal bleeding, liver disease or liver cancer, severe migraine headaches, or if you have ever had breast or uterine cancer, jaundice caused by birth control pills, a heart attack, a stroke, or a blood clot.

Taking birth control pills can increase your risk of blood clots, stroke, or heart attack, especially if you have certain other conditions, or if you are overweight.

Smoking can increase your risk of blood clot, stroke, or heart attack while taking birth control pills. You should not take ethinyl estradiol and norethindrone if you smoke and are older than 35 years of age.

Taking birth control pills can increase your risk of blood clots, stroke, or heart attack. You are even more at risk if you have high blood pressure, diabetes, high cholesterol, or if you are overweight. Your risk of stroke or blood clot is highest during your first year of taking birth control pills. Your risk is also high when you restart birth control pills after not taking them for 4 weeks or longer.

Smoking can greatly increase your risk of blood clots, stroke, or heart attack. Your risk increases the older you are and the more you smoke. You should not take combination birth control pills if you smoke and are over 35 years old.

Do not use if you are pregnant or think you might be pregnant. Tell your doctor right away if you become pregnant, or if you miss two menstrual periods in a row. If you have recently had a baby, wait at least 4 weeks before taking birth control pills.

You should not take birth control pills if you have:

• untreated or uncontrolled high blood pressure;
• heart disease (coronary artery disease, uncontrolled heart valve disorder, history of heart attack, stroke, or blood clot);
• a blood-clotting disorder or circulation problems;
• problems with your eyes, kidneys or circulation caused by diabetes;
• a history of hormone-related cancer such as breast or uterine cancer;
• unusual vaginal bleeding that has not been checked by a doctor;
• liver disease or liver cancer;
• severe migraine headaches (with aura, numbness, weakness, or vision changes), especially if you are older than 35;
• a history of jaundice caused by pregnancy or birth control pills; or
• if you smoke and are over 35 years old.

To make sure birth control pills are safe for you, tell your doctor if you have:

• high blood pressure, varicose veins;
• high cholesterol or triglycerides, or if you are overweight;
• a history of depression;
• underactive thyroid;
• gallbladder disease;
• diabetes;
• seizures or epilepsy;
• a history of irregular menstrual cycles;
• tuberculosis; or
• a history of fibrocystic breast disease, lumps, nodules, or an abnormal mammogram.

The hormones in birth control pills can pass into breast milk and may harm a nursing baby. This medication may also slow breast milk production. Do not use if you are breast feeding a baby.

• It is used to prevent pregnancy.
• It is used to treat pimples (acne).
• It may be given to you for other reasons. Talk with the doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Coughing up blood.
• Shortness of breath.
• Chest pain or pressure.
• Very bad dizziness or passing out.
• Very upset stomach or throwing up.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Swelling, warmth, numbness, change of color, or pain in a leg or arm.
• Very bad headache.
• Low mood (depression).
• Feeling very tired or weak.
• Very bad belly pain.
• Swelling.
• Not able to pass urine or change in how much urine is passed.
• A lump in the breast, breast soreness, or nipple discharge.
• Vaginal itching or discharge.
• Spotting or vaginal bleeding that is very bad or does not go away.
• Bulging eyes.
• Change in eyesight.
• Change in how contact lenses feel in the eyes.

How to Start Junel Fe 24

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

Table 1: Instructions for Administration of Junel Fe 24

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: • Junel Fe 24 active tablets are light yellow (Day 1 to Day 24). • Junel Fe 24 inactive tablets are brown (Day 25 to Day 28).	Day 1 Start: • Take first light yellow 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).
	Sunday Start: For each 28-day course, take in the following order: • Take the light yellow 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 Junel Fe 24. • 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.
Switching to Junel Fe 24 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 Junel Fe 24	Start Junel Fe 24:
• Transdermal patch	• On the day when next application would have been scheduled.
• Vaginal ring	• On the day when next insertion would have been scheduled
• Injection	• On the day when next injection would have been scheduled
• Intrauterine contraceptive	• On 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.
• Implant	• On the day of removal
Complete instructions on proper tablet usage are located in the FDA-approved patient labeling.

Starting Junel Fe 24 after Abortion or Miscarriage

First-trimester

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

Second-trimester

• Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Junel Fe 24 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 Junel Fe 24 [see Contraindications (4), Warnings and Precautions (5.1), and FDA-approved Patient Labeling].   Starting Junel Fe 24 after Childbirth • Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Junel Fe 24 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 Junel Fe 24 [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1 and 8.3)].

Missed Tablets

Table 2: Instructions for Missed Junel Fe 24 Tablets

• If one active tablet is missed in Weeks 1, 2 or 3	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.
• If two consecutive active tablets are missed in Week 1 or Week 2	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.
• If two consecutive active tablets are missed in Week 3 or Week 4 or three or more consecutive active tablets are missed at any time	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 light yellow tablet, handle this as a missed tablet [see FDA-Approved Patient Labeling].

Junel Fe 24 (norethindrone acetate and ethinyl estradiol tablets USP, 1 mg/0.02 mg and ferrous fumarate tablets) is available in blister packs.

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

• 24 light yellow, round, flat-faced, beveled-edge, unscored (active) tablets debossed with stylized b on one side and 977 on the other side and each containing 1 mg norethindrone acetate and 0.02 mg ethinyl estradiol. • 4 brown, round, flat-faced, beveled-edge, unscored (non-hormonal inert) tablets debossed with stylized b on one side and 247 on the other side and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.

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.

Pharmacodynamics

No specific pharmacodynamic studies were conducted with Junel Fe 24.

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 Junel Fe 24 tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 4 hours post-dose. 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 Junel Fe 24 tablets in 17 healthy female volunteers are provided in Figures 1 and 2, and Table 1.

Following multiple-dose administration of Junel Fe 24 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 Junel Fe 24 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 Junel Fe 24 Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17)

Figure 2. Mean Plasma Ethinyl Estradiol Concentration-Time Profiles Following Single- and Multiple-Dose Oral Administration of Junel Fe 24 Tablets to Healthy Female Volunteers under Fasting Condition (n = 17)

Table 1. Summary of Norethindrone (NE) and Ethinyl Estradiol (EE) Pharmacokinetics Following Single- and Multiple-Dose Oral Administration of Junel Fe 24 Tablets to Healthy Female Volunteers under Fasting Condition (n = 17)

* The harmonic mean (0.693/mean apparent elimination rate constant) is reported for t½, and the median (range) is reported for tmax. † The SHBG concentration reported here is the pre-dose concentration.
Regimen	Analyte	Arithmetic Mean* (% CV) by Pharmacokinetic Parameter
		Cmax (pg/mL)	tmax (hr)	AUC(0−24) (pg/mL•h)	Cmin (pg/mL)	t½ (hr)	Cavg (pg/mL)
Day 1 (Single Dose)	NE	8420 (31)	1.0 (0.7 to 4.0)	33390 (40)	--	--	--
	EE	64.5 (27)	1.3 (0.7 to 4.0)	465.4 (26)	--	--	--
	SHBG	--	--	--	57.5 (37)†	--	--
Day 24 (Multiple Dose)	NE	16400 (26)	1.3 (0.7 to 4.0)	88160 (30)	880 (51)	8.4	3670 (30)
	EE	81.9 (24)	1.7 (1.0 to 2.0)	701.3 (28)	11.4 (43)	14.5	29.2 (28)
	SHBG	--	--	--	144 (24)	--	--
Cmax = Maximum plasma concentration tmax = Time of Cmax Cmin = minimum plasma concentration at steady-state AUC(0−24) = Area under plasma concentration versus time curve from 0 to 24 hours t½ = Apparent first-order terminal elimination half-life Cavg = Average plasma concentration = AUC(0–24)/24 % CV = Coefficient of Variation (%) SHBG = Sex Hormone Binding Globulin (nmol/L)

Food Effect

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

[See Warnings and Precautions (5.2, 5.10) and Use in Specific Populations (8.1).]

How Supplied

Junel® Fe 24 (norethindrone acetate and ethinyl estradiol tablets USP, 1 mg/0.02 mg and ferrous fumarate tablets*) is available only in 28 tablets and packaged in cartons of 3 blister cards of 28 tablets each.

  NDC 0093-5328-62 Cartons of 3 blister cards (dispensers)

Each blister card contains in the following order:

• 24 light yellow, round, flat-faced, beveled-edge, unscored (active) tablets debossed with stylized b on one side and 977 on the other side and each containing 1 mg norethindrone acetate, USP and 0.02 mg ethinyl estradiol, USP. • 4 brown, round, flat-faced, beveled-edge, unscored (non-hormonal inert) tablets debossed with stylized b on one side and 247 on the other side and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.   *Ferrous fumarate tablets are not USP for dissolution and assay.

Storage Conditions

• Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. • Protect from light.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Junel® Fe 24 (norethindrone acetate and ethinyl estradiol tablets USP 1 mg/0.02 mg and ferrous fumarate tablets), 28 Tablet Blister Card x 3 Carton Text

  NDC 0093-5328-62 Three Blister Cards, 28 Tablets Each

Junel® Fe 24

(norethindrone acetate and

ethinyl estradiol tablets USP

1 mg/0.02 mg

and ferrous fumarate tablets*)

Pharmacist: Each foil pouch contains one combination “Patient Brief Summary/Detailed

Patient Package Insert,” which is to be provided to the patient with each prescription.

Provides 24 days of active therapy

Contains 3 blister cards, each containing a cycle of 28 tablets. Each of the light yellow

tablets contain norethindrone acetate, 1 mg and ethinyl estradiol, 0.02 mg. Each of the

4 brown tablets contain ferrous fumarate, 75 mg.

*Ferrous fumarate tablets are not USP for dissolution and assay.

Rx only

SHAPING

WOMEN’S HEALTH®

TEVA

JUNEL FE  24 norethindrone acetate and ethinyl estradiol and ferrous fumarate kit

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0093-5328

Packaging # Item Code Package Description 1 NDC:0093-5328-62 3 POUCH in 1 CARTON 1 NDC:0093-5328-28 1 BLISTER PACK in 1 POUCH 1 1 KIT in 1 BLISTER PACK

Quantity of Parts Part # Package Quantity Total Product Quantity Part 1 24  Part 2 4

Part 1 of 2 NORETHINDRONE ACETATE AND ETHINYL ESTRADIOL  norethindrone acetate and ethinyl estradiol tablet

Product Information Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength NORETHINDRONE ACETATE (NORETHINDRONE) NORETHINDRONE ACETATE 1 mg ETHINYL ESTRADIOL (ETHINYL ESTRADIOL) ETHINYL ESTRADIOL 0.02 mg

Inactive Ingredients Ingredient Name Strength ACACIA   SUCROSE   MALTODEXTRIN   D&C YELLOW NO. 10   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE   STARCH, CORN

Product Characteristics Color YELLOW (light yellow) Score no score Shape ROUND Size 6mm Flavor Imprint Code b;977 Contains

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090938 06/08/2015

Part 2 of 2 INERT  inert tablet

Product Information Route of Administration ORAL DEA Schedule

Inactive Ingredients Ingredient Name Strength FERROUS FUMARATE 75 mg CROSPOVIDONE (15 MPA.S AT 5%)   HYDROGENATED COTTONSEED OIL   CELLULOSE, MICROCRYSTALLINE

Product Characteristics Color BROWN Score no score Shape ROUND Size 6mm Flavor Imprint Code b;247 Contains

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090938 06/08/2015

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090938 06/08/2015

Labeler - Teva Pharmaceuticals USA, Inc. (001627975)

Revised: 09/2016   Teva Pharmaceuticals USA, Inc.