LO LOESTRIN FE

Warnings and Precautions ( 5.2 ) 04/2022

1 INDICATIONS AND USAGE 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 ( 1 ) The efficacy of Lo Loestrin Fe in women with a body mass index of > 35 kg/m 2 has not been evaluated ( 1 , 8.8 )

2 DOSAGE AND ADMINISTRATION 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 ) 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 [see Clinical Pharmacology (12.3) ] . 2.2 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 [see Warnings and Precautions (5.1) ] . 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. 2.3 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. 2.4 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 (suc …

3 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 ( 3 ): 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

4 CONTRAINDICATIONS Lo Loestrin Fe is contraindicated in females who are known to have or develop 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 (5.5) ] • Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.7) ] • Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions (5.8) ] Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions (5.2) ] Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3) ] Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.9) ] 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 (5.4) ] . A high risk of arterial or venous thrombotic diseases ( 4 ) Breast cancer ( 4 ) Liver tumors or liver disease ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and smoking [see Boxed Warning and Warnings and Precautions (5.1) ] Vascular events [see Warnings and Precautions (5.1) ] Liver disease [see Warnings and Precautions (5.3) ] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache The most common adverse reactions (≥ 2 percent) are nausea/vomiting (7 percent), headache (7 percent), bleeding irregularities (5 percent), dysmenorrhea (4 percent), weight change (4 percent), breast tenderness (4 percent), acne (3 percent), abdominal pain (3 percent), anxiety (2 percent) and depression (2 percent) ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Relevant studies of Risk of Breast Cancer with combined Oral Contraceptives 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. A multicenter phase 3 clinical trial evaluated the safety and efficacy of Lo Loestrin Fe for pregnancy prevention. The study was a one year, open-label, single-arm, uncontrolled study. A total of 1,660 women aged 18 to 45 were enrolled and took at least one dose of Lo Loestrin Fe [ s ee Clinical Studies (14) ] . Common Adverse Reactions ( ≥ 2 percent of all Treated Subjects ) : The most common adverse reactions reported by at least 2 percent of the 1,660 women using Lo Loestrin Fe were the following in order of decreasing incidence: nausea/vomiting (7 percent), headache (7 percent), bleeding irregularities (including metrorrhagia, irregular menstruation, menorrhagia, vaginal hemorrhage and dysfunctional uterine bleeding) (5 percent), dysmenorrhea (4 percent), weight fluctuation (4 percent), breast tenderness (4 percent), acne (3 percent), abdominal pain (3 percent), anxiety (2 percent), and depression (2 percent). Adverse Reactions Leading to Study Discontinuation : 10.7 percent of the women discontinued from the clinical trial due to an adverse reaction. Adverse reactions occurring in ≥1 percent of subjects leading to discontinuation of treatment were in decreasing order: menstrual irregularities (including metrorrhagia, irregular menstruation, menorrhagia and vaginal hemorrhage) (4 percent), headache/migraine (1 percent), mood disorder (including mood swings, depression, anxiety) (1 percent), and weight fluctuation (1 percent). Serious Adverse Reactions : deep vein thrombosis, ovarian vein thrombosis, cholecystitis. 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 never used COCs.

7 DRUG INTERACTIONS 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 ( 7.1 ) -- - ---------- ------ USE IN SPECIFIC POPULATIONS---- -- -- --------- ---- Lactation: Not recommended; Lo Loestrin Fe can decrease milk production ( 8.2 ) 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. 7.2 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. 7.3 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 [see Warnings and Precautions (5.4) ] . 7.4 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, Lo Loestrin Fe should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb reduction defects) following exposure to combined hormonal contraceptives (CHCs) before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively. Data Human Data Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy. 8. 2 Lactation Risk Summary Contraceptive hormones and/or metabolites are present in human milk. CHCs can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breastfeeding. [See also Dosage and Administration (2.2) .] The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Lo Loestrin Fe and any potential adverse effects on the breastfed child from Lo Loestrin Fe or from the underlying maternal condition. 8.4 Pediatric Use Safety and efficacy of Lo Loestrin Fe have been established in women of reproductive age. Safety and efficacy are expected to be the same in postpubertal adolescents under the age of 18 years as for users 18 years and older. Use of this product before menarche is not indicated. 8.5 Geriatric Use Lo Loestrin Fe has not been studied in postmenopausal women and is not indicated in this population. 8.6 Renal Impairment The pharmacokinetics of Lo Loestrin Fe has not been studied in subjects with renal impairment. 8.7 Hepatic Impairment No studies have been conducted to evaluate the effect of hepatic impairment on the disposition of Lo Loestrin Fe. However, 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 [ s ee Contraindications (4) and Warnings and Precautions (5.3) ] . 8.8 Body Mass Index The safety and efficacy of Lo Loestrin Fe in women with a body mass index (BMI) >35 kg/m 2 has not been evaluated [ s ee Clinical Studies (14) ] .

12.1 Mechanism of Action CHCs prevent pregnancy primarily by suppressing ovulation.

11 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)-].

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.

16 H OW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Lo Loestrin ® Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl estradiol tablets and ferrous fumarate tablets) is available in blister cards (dispensers) containing 28 tablets: NDC 0430-0420-14 Cartons of 5 blister cards (dispensers) NDC 0430-0420-60 Cartons of 30 blister cards (dispensers) Each blister card (28 tablets) contains in the following order: 24 blue, round tablets (active) imprinted with “WC” on one side and “421” on the other and each containing 1 mg norethindrone and 10 mcg ethinyl estradiol 2 white, hexagonal tablets (active) imprinted with “WC” on one side and “422” on the other and each containing 10 mcg ethinyl estradiol 2 brown, round tablets (non-hormonal placebo) imprinted with “WC” on one side and “624” on the other and each containing 75 mg ferrous fumarate 16.2 Storage Conditions Store at 25o C (77o F); excursions permitted to 15 - 30o C (59 - 86o F) [see USP Controlled Room Temperature]. Keep this drug and all drugs out of the reach of children.

16.1 How Supplied Lo Loestrin ® Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl estradiol tablets and ferrous fumarate tablets) is available in blister cards (dispensers) containing 28 tablets: NDC 0430-0420-14 Cartons of 5 blister cards (dispensers) NDC 0430-0420-60 Cartons of 30 blister cards (dispensers) Each blister card (28 tablets) contains in the following order: 24 blue, round tablets (active) imprinted with “WC” on one side and “421” on the other and each containing 1 mg norethindrone and 10 mcg ethinyl estradiol 2 white, hexagonal tablets (active) imprinted with “WC” on one side and “422” on the other and each containing 10 mcg ethinyl estradiol 2 brown, round tablets (non-hormonal placebo) imprinted with “WC” on one side and “624” on the other and each containing 75 mg ferrous fumarate