Kaitlib Fe

1 INDICATIONS AND USAGE Kaitlib Fe is a combination of norethindrone, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 ) The efficacy in females of reproductive potential with a body mass index (BMI) of >35 kg/m 2 has not been evaluated. ( 1 , 8.8 ) Kaitlib™ Fe (norethindrone and ethinyl estradiol chewable tablets and ferrous fumarate chewable tablets) is indicated for use by women to prevent pregnancy. The efficacy of Kaitlib Fe in women with a body mass index (BMI) of > 35 kg/m 2 has not been evaluated.

2 DOSAGE AND ADMINISTRATION Chew one tablet without water at the same time every day. ( 2.1 ) Take tablets in the order directed on the blister pack. ( 2.1 ) 2.1 How to Take Kaitlib Fe To achieve maximum contraceptive effectiveness, Kaitlib Fe must be taken exactly as directed. Chew and swallow one tablet without water 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. Kaitlib Fe may be administered without regard to meals [see CLINICAL PHARMACOLOGY ( 12.3 )]. 2.2 How to Start Kaitlib Fe Instruct the patient to begin taking Kaitlib Fe on Day 1 of her menstrual cycle (that is, the first day of her menstrual bleeding). One light green tablet should be taken daily for 24 consecutive days followed by one brown tablet daily for 4 consecutive days . Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days if she starts taking Kaitlib Fe other than on the first day of her menstrual cycle. For postpartum women who do not breastfeed or after a second trimester abortion, Kaitlib 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 combined oral contraceptives (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. If the patient is switching from a combination hormonal method such as: o Another pill o Vaginal ring o Patch Instruct her to take the first light green pill on the day she would have started a new cycle of her previous birth control pack (Day 1). If she previously used a vaginal ring or transdermal patch, she should start using Kaitlib Fe on the day she would have restarted the ring or patch. Instruct the patient to use a non-hormonal back-up method such as a condom and spermicide for the first 7 days. If the patient is switching from a progestin-only method such as: o Progestin-only pill o Implant o Intrauterine system o Injection Instruct her to take the first light green pill on the day she would have taken her next progestin-only pill or on the day of removal of her implant or intrauterine system or on the day when she would have had her next injection. Instruct the patient to use a non-hormonal back-up method such as a condom and spermicide for the first 7 days. 2.3 Missed Doses Table 1. Instructions for Missed Kaitlib Fe Tablets If one light green tablet is missed Take the missed tablet as soon as possible. Take the next tablet at the regular time. Continue taking one tablet a day until the pack is finished. Additional nonhormonal contraception (such as condoms) is not needed. If two light green tablets in a row are missed in Week 1 or Week 2 of the tablet pack Take the two missed tablets as soon as possible, and the next two tablets the next day. Continue taking one tablet a day until the pack is finished. Use additional nonhormonal contraception (such as condoms) until hormonal tablets have been taken for 7 days after missing tablets. If two light green tablets in a row are missed in Week 3 or Week 4 of the tablet pack Throw away the remainder of the tablet pack. Start a new tablet pack the same day. Use additional nonhormonal contraception (such as condoms) until hormonal tablets have been taken for 7 days after missing tablets. If three or more light green tablets in a row are missed Throw away the missed tablets. Continue taking one tablet every day as indicated on the pack until the pack is finished. Bleeding may occur during the week following the missed tablets. Use additional nonhormonal contraception (such as condoms) until hormonal tablets have been taken for 7 days after missing tablets. If any of the four brown tablets are missed Throw away the missed tablets. Continue taking the remaining tablets until th…

5 WARNINGS AND PRECAUTIONS Vascular risks: Stop Kaitlib Fe if a thrombotic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery in women who are not breastfeeding.( 5.1 ) Liver disease: Discontinue if jaundice occurs. ( 5.3 ) High blood pressure: Do not prescribe for women with uncontrolled hypertension or hypertension with vascular disease. ( 5.5 ) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Kaitlib Fe. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.5 ) Headache: Evaluate significant change in headaches and discontinue if indicated. ( 5.8 ) Uterine bleeding: Evaluate irregular bleeding or amenorrhea. ( 5.9 ) 5.1 Thrombotic and Other Vascular Events Stop Kaitlib Fe if an arterial or deep venous thrombotic (VTE) event occurs. Although the 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 excess 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 Kaitlib 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 Kaitlib 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 among older (>35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. Stop Kaitlib 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 Kaitlib 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 Kaitlib 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/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk…

4 CONTRAINDICATIONS A high risk of arterial or venous thrombotic diseases. ( 4 ) Undiagnosed abnormal uterine bleeding. ( 4 ) Breast cancer. ( 4 ) Liver tumors or liver disease. ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir ( 4 ) Kaitlib Fe (norethindrone and ethinyl estradiol chewable tablets and ferrous fumarate chewable tablets) 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: o Smoke, if over age 35 [see BOXED WARNING , and WARNINGS AND PRECAUTIONS ( 5.1 .)] o Have deep vein thrombosis or pulmonary embolism, now or in the past [see WARNINGS AND PRECAUTIONS ( 5.1 )] o Have cerebrovascular disease [see WARNINGS AND PRECAUTIONS ( 5.1 )] o Have coronary artery disease [see WARNINGS AND PRECAUTIONS ( 5.1 )] o 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 )] o Have inherited or acquired hypercoagulopathies [see WARNINGS AND PRECAUTIONS ( 5.1 )] o Have uncontrolled hypertension [see WARNINGS AND PRECAUTIONS ( 5.5 )] o Have diabetes with vascular disease [see WARNINGS AND PRECAUTIONS ( 5.7 )] o 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 ) , USE IN SPECIFIC POPULATIONS ( 8.7 ) , and CLINICAL PHARMACOLOGY ( 12.3 )] 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 )]

7 DRUG INTERACTIONS 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 ) No drug-drug interaction studies were conducted with Kaitlib Fe. 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 with 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 in Plasma Levels of Ethinyl Estradiol Associated with Co-Administered Drugs Co-administration of atorvastatin and certain combination oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. 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 Kaitlib 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 (e.g., 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, Kaitlib 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 COCs 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.

8.2 Lactation Risk Summary Contraceptive hormones and/or metabolites are present in human milk. COCs can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breast-feeding [ see DOSAGE and ADMINISTRATION ( 2.2 ) ]. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for Kaitlib Fe and any potential adverse effects on the breast-fed child from Kaitlib Fe or from the underlying maternal condition.

6 ADVERSE REACTIONS The most common adverse reactions (≥ 2%) are nausea/vomiting (8.8%), headaches/migraine (7.5%), depression/mood complaints (4.1%), dysmenorrhea (3.9%), acne (3.2%), anxiety symptoms (2.4%), breast pain/tenderness (2.4%), and increased weight (2.3%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A phase 3 clinical trial evaluated the safety and efficacy of Kaitlib Fe for pregnancy prevention. The study was a multicenter, non-comparative, open-label study with a treatment duration of 12 months (thirteen 28-day cycles). A total of 1,677 women aged 18 to 46 were enrolled and took at least one dose of Kaitlib Fe. Adverse Reactions Leading to Study Discontinuation 8.5% of the women discontinued from the clinical trial due to an adverse reaction. The most common adverse reactions leading to discontinuation were nausea (1.0%), weight increase (0.8%), acne (0.8%), metrorrhagia (0.7%), altered mood (0.4%), hypertension (0.4%), irritability (0.3%), migraine (0.3%), decreased libido (0.3%) and mood swings (0.3%). Common Adverse Reactions (≥ 2% of all treated subjects) Nausea/vomiting (8.8%), headaches/migraine (7.5%), depression/mood complaints (4.1%), dysmenorrhea (3.9%), acne (3.2%), anxiety symptoms (2.4%), breast pain/tenderness (2.4%), and increased weight (2.3%). Serious Adverse Reactions Hypertension, depression, cholecystitis, and deep vein thrombosis. 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. Fiq 1