D ESCRIPTION Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl estradiol tablets and ferrous fumarate tablets) provides an oral contraceptive regimen consisting of 24 blue active tablets and 2 white active tablets that contain the active ingredients specified for each tablet below, followed by 2 non-hormonal placebo tablets: 24 blue, round tablets each containing 1 mg norethindrone acetate and 10 mcg ethinyl estradiol 2 white, hexagonal tablets each containing 10 mcg ethinyl estradiol 2 brown, round tablets each containing 75 mg ferrous fumarate Each blue tablet also contains the inactive ingredients mannitol, microcrystalline cellulose, FD&C Blue No. 1 Aluminum Lake, sodium starch glycolate, magnesium stearate, povidone, vitamin E and lactose monohydrate. Each white tablet also contains the inactive ingredients mannitol, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, povidone, vitamin E and lactose monohydrate. Each brown tablet contains ferrous fumarate, mannitol, povidone, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, sucralose and spearmint flavor. The ferrous fumarate tablets do not serve any therapeutic purpose. Ferrous fumarate tablets are not USP for dissolution and assay. The empirical formula of ethinyl estradiol is C 20 H 24 O 2 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 empirical formula of norethindrone acetate is C 22 H 28 O 3 and the structural formula is: The chemical name of norethindrone acetate is [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-]. The chemical name of ethinyl estradiol is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17)-]. The chemical name of norethindrone acetate is [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17)-].

Lo Loestrin ® Fe is indicated for use by women to prevent pregnancy [ see Clinical Studies (14) ] . The efficacy of Lo Loestrin Fe in women with a body mass index (BMI) of > 35 kg/m 2 has not been evaluated. Lo Loestrin Fe is a combination of norethindrone acetate, a progestin, and ethinyl estradiol, an estrogen, indicated for use by women to prevent pregnancy The efficacy of Lo Loestrin Fe in women with a body mass index of > 35 kg/m 2 has not been evaluated

DOSAGE FORM S AND STRENGTH S Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl estradiol tablets and ferrous fumarate tablets) is available in blister packs. Each blister pack (28 tablets) contains in the following order: 24 blue, round (active) tablets imprinted with “WC” on one side and “421” on the other and each containing 1 mg norethindrone acetate and 10 mcg ethinyl estradiol. 2 white, hexagonal (active) tablets imprinted with “WC” on one side and “422” on the other and each containing 10 mcg ethinyl estradiol. 2 brown, round (non-hormonal placebo) tablets imprinted with “WC” on one side and “624” on the other and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose. Lo Loestrin Fe consists of 28 tablets in the following order: 24 blue tablets (active), each containing 1 mg norethindrone acetate and 10 mcg ethinyl estradiol 2 white tablets (active), each containing 10 mcg ethinyl estradiol 2 brown tablets (non-hormonal placebo), each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose

Take one tablet by mouth at the same time every day for 28 days Take tablets in the order directed on the blister pack 2.1 How to Take Lo Loestrin Fe To achieve maximum contraceptive effectiveness, Lo Loestrin Fe must be taken exactly as directed. Take one tablet by mouth at the same time every day. Tablets must be taken in the order directed on the blister pack. Tablets should not be skipped or taken at intervals exceeding 24 hours. Lo Loestrin Fe tablets may be administered without regard to meals

How to Start Lo Loestrin Fe Instruct the patient to begin taking Lo Loestrin Fe on Day 1 of her menstrual cycle (that is, the first day of her menstrual bleeding). One blue tablet should be taken daily for 24 consecutive days, followed by one white tablet daily for 2 consecutive days, followed by one brown tablet daily for 2 consecutive days. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days if she starts taking Lo Loestrin Fe other than on the first day of her menstrual cycle. For postpartum women who do not breastfeed or after a second trimester abortion, Lo Loestrin Fe may be started no earlier than 4 weeks postpartum. Recommend use of a non-hormonal back-up method for the first 7 days. When COCs are used during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered . The possibility of ovulation and conception before starting COCs should also be considered. Lo Loestrin Fe may be initiated immediately after a first-trimester abortion or miscarriage; if the patient starts Lo Loestrin Fe immediately, additional contraceptive measures are not needed

Switching from another H ormonal M ethod of C ontraception If the patient is switching from a combination hormonal method such as: ○ Another pill ○ Vaginal ring ○ Patch Instruct her to take the first blue 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 Lo Loestrin Fe. If she previously used a vaginal ring or transdermal patch, she should start using Lo Loestrin 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 Instruct her to take the first blue tablet on the day she would have taken her next progestin-only pill, or had her next injection 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

Missed Doses Table 1: Instructions for Missed Lo Loestrin Fe Tablets in a Monthly Dosing Regimen If one blue tablet is missed Take the tablet as soon as possible, even if two tablets are taken in one day. Continue taking one tablet a day until the pack is finished. If two consecutive blue tablets are missed in Week 1 or Week 2 Take the two missed tablets as soon as possible, and the next two tablets the next day. Continue taking the remaining tablets, one tablet a day until the pack is finished. Use ad ditional non-hormonal contraception (such as condoms and spermicide) for 7 consecutive days after missing tablets. If two consecutive tablets (blue or white) are missed in Week 3 or Week 4 Throw out the rest of the pack and start a new pack the same day. A withdrawal bleed may not occur. Use ad ditional non-hormonal contraception (such as condoms and spermicide) for 7 consecutive days after missing tablets. If three or more consecutive tablets (blue or white) are missed at any time Throw out the rest of the pack and start a new pack that same day. A withdrawal bleeding may not occur. Use a dditional non-hormonal contraception (such as condoms and spermicide) for 7 consecutive days after missing tablets. If either of the brown tablets in Week 4 are missed Throw out the tablet you missed. Start a new pack on the same day a new pack is usually started

Advice in Case of Gastrointestinal Disturbances If the patient vomits or has diarrhea (within 3 to 4 hours after she takes a blue or white pill), she should follow the instructions in Missed Doses .

Vascular risks: Stop Lo Loestrin Fe if a thrombotic event occurs. Stop Lo Loestrin Fe at least 4 weeks before through 2 weeks after major surgery. Start Lo Loestrin Fe no earlier than 4 weeks after delivery, in women who are not breastfeeding Liver disease: Discontinue Lo Loestrin Fe if jaundice occurs High blood pressure: Do not prescribe Lo Loestrin Fe for women with uncontrolled hypertension or hypertension with vascular disease. Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Lo Loestrin Fe. Consider an alternative contraceptive method for women with uncontrolled dyslipidemia Headache: Evaluate significant change in headaches and discontinue Lo Loestrin Fe if indicated Uterine bleeding: Evaluate irregular bleeding or amenorrhea 5.1 Thrombotic and Other Vascular Events Stop Lo Loestrin Fe if an arterial or deep venous thrombotic event occurs. Although use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The risk is highest during the first year of use of a COC. 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. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued. If feasible, stop Lo Loestrin Fe at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start Lo Loestrin Fe no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. 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 (> 35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with underlying risk factors. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. Stop Lo Loestrin Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately

Malignant Neoplasms Breast Cancer Lo Loestrin Fe is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive . 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 . 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

Liver Disease Discontinue Lo Loestrin Fe if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. 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. 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 (>8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users. Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use

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 Lo Loestrin Fe prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir . Lo Loestrin Fe can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen

High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop Lo Loestrin Fe if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. 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. 6 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users

C arbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking Lo Loestrin 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

Headache If a woman taking Lo Loestrin Fe develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Lo Loestrin Fe if indicated. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC

Bleeding Irregularities and Amenorrhea 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. The clinical trial that evaluated the efficacy of Lo Loestrin Fe also assessed unscheduled bleeding and/or spotting. The participants in this 12-month clinical trial (N = 1,582 who had at least one post-treatment evaluation) completed over 15,000 cycles of exposure. A total of 1,257 women (85.9 percent) experienced unscheduled bleeding and/or spotting at some time during Cycles 2 to 13 of this study. The incidence of unscheduled bleeding and/or spotting was highest during Cycle 2 (53 percent) and lowest at Cycle 13 (36 percent). Among these women, the mean number of days of unscheduled bleeding and/or spotting during a 28-day cycle ranged from 1.8 to 3.2 days. Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over the one year study, with an average of less than 2 days per cycle. Women who are not pregnant and use Lo Loestrin Fe may experience amenorrhea (absence of scheduled and unscheduled bleeding/spotting). In the clinical trial with Lo Loestrin Fe, the incidence of amenorrhea increased from 32 percent in Cycle 1 to 49 percent by Cycle 13. 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. Some women may experience amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was preexistent

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. Lo Loestrin Fe use should be discontinued if pregnancy is confirmed. Administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy

1 Depression Women with a history of depression should be carefully observed and Lo Loestrin Fe discontinued if depression recurs to a serious degree

Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid binding globulin increase with use of COCs

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

Other Conditions In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 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 COCs.

No drug-drug interaction studies were conducted with Lo Loestrin Fe. 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 -- - ---------- ------ USE IN SPECIFIC POPULATIONS---- -- -- --------- ---- Lactation: Not recommended; Lo Loestrin Fe can decrease milk production 7.1 Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Products If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: barbiturates bosentan carbamazepine felbamate griseofulvin oxcarbazepine phenytoin rifampin St. John’s wort topiramate HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors : Significant changes (increase or decrease) in the plasma levels of the estrogen and progestin have been noted in some cases of co-administration of HIV 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. Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations

Increase i n Plasma Levels of Ethinyl Estradiol Associated with Co-Administered Drugs Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20 percent. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels

Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Lo Loestrin Fe with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations

Changes in Plasma Levels of Co-Administered Drugs COCs containing some synthetic estrogens (for example, 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. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.