Norethindrone Acetate and Ethinyl Estradiol, Ethinyl Estradiol and Ferrous Fumarate

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 )

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

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 )

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 ( 5.1 ) Liver disease: Discontinue Lo Loestrin Fe if jaundice occurs ( 5.3 ) High blood pressure: Do not prescribe Lo Loestrin Fe for women with uncontrolled hypertension or hypertension with vascular disease. ( 5.5 ) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Lo Loestrin Fe. Consider an alternative contraceptive method for women with uncontrolled dyslipidemia ( 5.7 ) Headache: Evaluate significant change in headaches and discontinue Lo Loestrin Fe if indicated ( 5.8 ) Uterine bleeding: Evaluate irregular bleeding or amenorrhea ( 5.9 )

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.

5.2 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 [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.

5.3 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.

5.4 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 [see Contraindications (4) ] . Lo Loestrin Fe can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.5 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. 5.7 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.

5.8 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.

5.9 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). […]

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 AbbVie 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.

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.

8.1 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) ] .

CHCs prevent pregnancy primarily by suppressing ovulation.