Mibelas 24 Fe: Package Insert and Label Information

MIBELAS 24 FE — norethindrone acetate, ethinyl estradiol and ferrous fumarate
Lupin Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

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/m² has not been evaluated.

2 DOSAGE AND ADMINISTRATION

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 next day after ingestion of the last brown tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of Mibelas 24 Fe is started later than the day following administration of the last brown tablet, the patient should use another method of contraception until she has taken a white Mibelas 24 Fe tablet daily for 7 consecutive days.

For postpartum women who do not breastfeed or after a second trimester abortion, start Mibelas 24 Fe no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts on Mibelas 24 Fe 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 Mibelas 24 Fe for 7 consecutive days.

Mibelas 24 Fe may be initiated immediately after a first-trimester abortion or miscarriage; if the patient starts Mibelas 24 Fe 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 Mibelas 24 Fe 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 Mibelas 24 Fe.
• If she previously used a vaginal ring or transdermal patch, she should start using Mibelas 24 Fe 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 Mibelas 24 Fe 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 Mibelas 24 Fe 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 Mibelas 24 Fe 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

Mibelas 24 Fe is available in carton (NDC 68180-911-73) containing three pouches, each pouch containing a bllister 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.

4 CONTRAINDICATIONS

Mibelas 24 Fe is contraindicated in females who are known to have or develop the following conditions:

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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

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o All women over age 35 with migraine headache [see WARNINGS AND PRECAUTIONS (5.6)]

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5 WARNINGS AND PRECAUTIONS

5.1 Thromboembolic Disorders and Other Vascular Problems

Stop Mibelas 24 Fe if an arterial or deep venous thrombotic event (VTE) occurs. Stop Mibelas 24 Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

If feasible, stop Mibelas 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.

Start Mibelas 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 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 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 Mibelas 24 Fe 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 Mibelas 24 Fe if jaundice develops.

Liver Tumors

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

5.4 High Blood Pressure

Mibelas 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 Mibelas 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.

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 Mibelas 24 Fe. 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 Mibelas 24 Fe develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Mibelas 24 Fe if indicated.

Consider discontinuation of Mibelas 24 Fe 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 Mibelas 24 Fe 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 Mibelas 24 Fe if depression recurs to a serious degree.

​ 5.11 Malignant Neoplasms

​ Breast Cancer
Mibelas 24 Fe is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally-sensitive [see CONTRAINDICATIONS (4)].
Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use[see ADVERSE REACTIONS (6.2) ].
Cervical Cancer
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.