Norethindrone Acetate and Ethinyl Estradiol: Package Insert and Label Information

NORETHINDRONE ACETATE AND ETHINYL ESTRADIOL — norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets
Xiromed, LLC

Structural Formula — Ethinyl EstradiolStructural Formula — Norethindrone AcetateFigure 1Figure 2Table 1Pregnancy Riskblisternore-outer-box

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

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets is 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.

2 DOSAGE AND ADMINISTRATION

2.1 How to Take Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets

To achieve maximum contraceptive effectiveness, norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets must be taken exactly as directed. Instruct patients to take one tablet by mouth at the same time every day. The tablet should 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]. Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may be administered without regard to meals [see Clinical Pharmacology (12.3)].

2.2 How to Start Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets

Instruct the patient to begin taking norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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

Day 1 Start During the first cycle of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets use, instruct the patient to take one white norethindrone acetate and ethinyl estradiol tablet daily, beginning on Day one (1) of her menstrual cycle (the first day of menstruation is Day one). She should take one white norethindrone acetate and ethinyl estradiol tablet daily for 24 consecutive days, followed by one brown ferrous fumarate tablet daily on days 25 through 28. Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets use, instruct the patient to take one white norethindrone acetate and ethinyl estradiol tablet daily, beginning on the first Sunday after the onset of her menstrual period. She should take one white norethindrone acetate and ethinyl estradiol tablet daily for 24 consecutive days, followed by one brown ferrous fumarate tablet daily on days 25 through 28. Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets should be taken in the order directed on the package at the same time each day. Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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 norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her white norethindrone acetate and ethinyl estradiol tablets on the next day after ingestion of the last brown ferrous fumarate tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets is started later than the day following administration of the last brown ferrous fumarate tablet, the patient should use another method of contraception until she has taken a white norethindrone acetate and ethinyl estradiol tablet daily for 7 consecutive days.

For postpartum women who do not breastfeed or after a second trimester abortion, start norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts on norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets for 7 consecutive days.

Norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets may be initiated immediately after a first-trimester abortion or miscarriage; if the patient starts norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets immediately, additional contraceptive measures are not needed.

2.3 Switching from another Hormonal Method of Contraception

If the patient is switching from a combination hormonal method such as:

— Another pill

— Vaginal Ring

— Patch

  • Instruct her to take the first white norethindrone acetate and ethinyl estradiol tablet on the day she would have taken her next COC pill. She should not continue taking the tablets from her previous birth control pack, and should not skip any days between packs. If she does not have a withdrawal bleed, rule out pregnancy before starting norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets.
  • If she previously used a vaginal ring or transdermal patch, she should start using norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets on the day she would have resumed the previous product.

If the patient is switching from a progestin-only method such as a:

— Progestin-only pill

— Implant

— Intrauterine system

— Injection

  • She may switch any day from a progestin-only pill; instruct her to take the first white norethindrone acetate and ethinyl estradiol tablet on the day she would have taken her next progestin-only pill. She should use a non-hormonal method of contraception for 7 consecutive days.
  • If switching from an implant or injection, start the first white norethindrone acetate and ethinyl estradiol tablet on the day her next injection would have been due or on the day of removal of her implant.
  • If switching from an IUD, depending on the timing of removal, back-up contraception may be needed.

2.4 Advice in Case of Gastrointestinal Disturbances

If the patient vomits or has diarrhea (within 3 to 4 hours after she takes a white norethindrone acetate and ethinyl estradiol tablet), she should follow the instructions in the “What to Do if You Miss Tablets” section [see FDA-approved patient labeling].

3 DOSAGE FORMS AND STRENGTHS

Norethindrone Acetate and Ethinyl Estradiol Tablets and Ferrous Fumarate Tablets, 1 mg/20 mcg is available in blister packs.

Each blister pack contains 28 tablets in the following order:

  • 24 white, round, (active) chewable tablets imprinted with “XI” on one side and “T4” on the other side, and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.
  • 4 brown, round (non-hormonal placebo) tablets imprinted with “XI” on one side and “12” on the other side, and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.

4 CONTRAINDICATIONS

Do not prescribe norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets 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:
    • Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)]
    • Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)]
    • Have cerebrovascular disease [see Warnings and Precautions (5.1)]
    • Have coronary artery disease [see Warnings and Precautions (5.1)]
    • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)]
    • Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)]
    • Have uncontrolled hypertension [see Warnings and Precautions (5.3)]
    • Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.5)]
    • Have headaches with focal neurological symptoms or have migraine headaches with aura
      • All women over age 35 with migraine headache [see Warnings and Precautions (5.6)]
  • Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.2)]
  • Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.7)]
  • Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.8) 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 (5.10)]
  • 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

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 womanyears. 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 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), 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 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 intraabdominal 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

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 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 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, 24-35% 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.

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