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CLINICAL PHARMACOLOGY Mechanism Of Action COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation. Pharmacodynamics No specific pharmacodynamic studies were conducted with TAYTULLA. Pharmacokinetics Absorption In a single-dose, crossover clinical study conducted in 39 healthy, non-smoking premenopausal women under fasting condition, NA/EE capsules were bioequivalent to norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets (24-day regimen tablets) based on the exposure (AUC) and peak concentration (Cmax) of norethindrone and ethinyl estradiol. Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, because the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are rapidly absorbed from norethindrone acetate/ethinyl estradiol tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 4 hours post-dose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol. The plasma norethindrone and ethinyl estradiol pharmacokinetics following single-and multiple-dose administrations of norethindrone acetate/ethinyl estradiol tablets in 17 healthy female volunteers are provided in Figures 1 and 2, and Table 1. Following multiple-dose administration of norethindrone acetate/ethinyl estradiol tablets, mean maximum concentrations of norethindrone and ethinyl estradiol were increased by 95% and 27%, respectively, as compared to single-dose administration. Mean norethindrone and ethinyl estradiol exposures (AUC values) were increased by 164% and 51% respectively, as compared to single-dose administration of norethindrone acetate/ethinyl estradiol tablets. Steady-state with respect to norethindrone was reached by Day 17 and steady-state with respect to ethinyl estradiol was reached by Day 13. Mean SHBG concentrations were increased by 150% from baseline (57.5 nmol/L) to 144 nmol/L at steady-state. Figure 1: Mean Plasma Norethindrone Concentration-Time Profiles Following Single-and Multiple-Dose Oral Administration of Norethindrone Acetate/Ethinyl Estradiol Tablets to Healthy Female Volunteers under Fasting Condition (n = 17) Figure 2: Mean Plasma Ethinyl Estradiol Concentration-Time Profiles Following Single-and Multiple-Dose Oral Administration of Norethindrone Acetate/Ethinyl Estradiol Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17) Table 1: Summary of Norethindrone (NE) and Ethinyl Estradiol (EE) Pharmacokinetics Following Single-and Multiple-Dose Oral Administration of Norethindrone Acetate/Ethinyl Estradiol Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17) Regimen Analyte Arithmetic Meana (% CV) by Pharmacokinetic Parameter Cmax (pg/mL) tmax (hr) AUC(0-24) (pg/mL•h) Cmin (pg/mL) t½ (hr) Cavg (pg/mL) Day 1 (Single Dose) NE 8420 (31) 1.0 (0.7-4.0) 33390 (40) -- -- -- EE 64.5 (27) 1.3 (0.7-4.0) 465.4 (26) -- -- -- SHBG -- -- -- 57.5 (37)b -- -- Day 24 (Multiple Dose) NE 16400 (26) 1.3 (0.7-4.0) 88160 (30) 880 (51) 8.4 3670 (30) EE 81.9 (24) 1.7 (1.0-2.0) 701.3 (28) 11.4 (43) 14.5 29.2 (28) SHBG -- -- -- 144 (24) -- -- Cmax = Maximum plasma concentration tmax = Time of Cmax Cmin = minimum plasma concentration at steady-state AUC(0-24) = Area under plasma concentration versus time curve from 0 to 24 hours t½ = Apparent first-order terminal elimination half-life Cavg = Average plasma concentration = AUC(0–24)/24 % CV = Coefficient of Variation (%) SHBG = Sex Hormone Binding Globulin (nmol/L) aThe harmonic mean (0.693/mean apparent elimination rate constant) is reported for t½, and the median (range) is reported for tmax. bThe SHBG concentration reported here is the pre-dose concentration. Food Effect TAYTULLA may be administered without regard to meals. A single-dose administration of NA/EE capsules with food in 38 healthy, non-smoking premenopausal women decreased the maximum concentration of norethindrone and ethinyl estradiol by 38% and 33%, respectively. Food intake did not affect the extent of ethinyl estradiol absorption, but increased the extent of norethindrone absorption by 19%. Distribution Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (>95%); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis. Metabolism Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation. Excretion Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of norethindrone acetate/ethinyl estradiol tablets are approximately 8 hours and 14 hours, respectively. Drug Interactions No drug-drug interaction studies were conducted with TAYTULLA. Clinical Studies The data presented in Section 14 are from a clinical trial conducted with a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets. TAYTULLA capsules are bioequivalent to these norethindrone acetate/ethinyl estradiol tablets. In a clinical study, 743 women 18 to 45 years of age were studied to assess the efficacy of norethindrone acetate/ethinyl estradiol tablets, for up to six 28-day cycles providing a total of 3,823 treatment-cycles of exposure. The racial demographic of all enrolled women was: 70% Caucasian, 16% African-American, 10% Hispanic, 2% Asian and 2% Other. Women with body mass index (BMI) greater than 35 mg/m² were excluded from the study. The weight range for those women treated was 90 to 260 pounds, with a mean weight of 147 pounds. Among the women in the study, about 40% had not used hormonal contraception immediately prior to enrolling in this study. A total of 583 women completed 6 cycles of treatment. There were a total of 5 on-treatment pregnancies in 3,565 treatment cycles during which no backup contraception was used. The Pearl Index for norethindrone acetate/ethinyl estradiol tablets was 1.82 (95% confidence interval 0.59 4.25).

CLINICAL PHARMACOLOGY Mechanism Of Action COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation. Pharmacodynamics No specific pharmacodynamic studies were conducted with LOESTRIN 24 Fe. Pharmacokinetics Absorption Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, because the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are rapidly absorbed from LOESTRIN 24 Fe tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 4 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol. The plasma norethindrone and ethinyl estradiol pharmacokinetics following single-and multiple-dose administrations of LOESTRIN 24 Fe tablets in 17 healthy female volunteers are provided in Figures 1 and 2, and Table 1. Following multiple-dose administration of LOESTRIN 24 Fe tablets, mean maximum concentrations of norethindrone and ethinyl estradiol were increased by 95% and 27%, respectively, as compared to single-dose administration. Mean norethindrone and ethinyl estradiol exposures (AUC values) were increased by 164% and 51% respectively, as compared to single-dose administration of LOESTRIN 24 Fe tablets. Steady-state with respect to norethindrone was reached by Day 17 and steady-state with respect to ethinyl estradiol was reached by Day 13. Mean SHBG concentrations were increased by 150% from baseline (57.5 nmol/L) to 144 nmol/L at steady-state. Figure 1: Mean Plasma Norethindrone Concentration-Time Profiles Following Single-and Multiple-Dose Oral Administration of LOESTRIN 24 Fe Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17) Figure 2: Mean Plasma Ethinyl Estradiol Concentration-Time Profiles Following Single-and Multiple-Dose Oral Administration of LOESTRIN 24 Fe Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17) Table 1: Summary of Norethindrone (NE) and Ethinyl Estradiol (EE) Pharmacokinetics Following Single-and Multiple-Dose Oral Administration of LOESTRIN 24 Fe Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17) Regimen Analyte Arithmetic Meana (% CV) by Pharmacokinetic Parameter Cmax (pg/mL) tmax (hr) AUC(0-24) (pg/mL•h) Cmin (pg/mL) t½(hr) Cavg (pg/mL) Day 1 (Single Dose) NE 8420 (31) 1.0 (0.7-4.0) 33390 (40) -- -- -- EE 64.5 (27) 1.3 (0.7-4.0) 465.4 (26) -- -- -- SHBG -- -- -- 57.5 (37)b -- -- Day 24 (Multiple Dose) NE 16400 (26) 1.3 (0.7-4.0) 88160 (30) 880 (51) 8.4 3670 (30) EE 81.9 (24) 1.7 (1.0-2.0) 701.3 (28) 11.4 (43) 14.5 29.2 (28) SHBG -- -- -- 144 (24) -- -- Cmax = Maximum plasma concentration tmax = Time of Cmax Cmin = minimum plasma concentration at steady-state AUC(0-24) = Area under plasma concentration versus time curve from 0 to 24 hours t½ = Apparent first-order terminal elimination half-life Cavg = Average plasma concentration = AUC(0–24)/24 % CV = Coefficient of Variation (%) SHBG = Sex Hormone Binding Globulin (nmol/L) aThe harmonic mean (0.693/mean apparent elimination rate constant) is reported for t½, and the median (range) is reported for tmax. bThe SHBG concentration reported here is the pre-dose concentration. Food Effect A single-dose administration of LOESTRIN 24 Fe tablet with food decreased the maximum concentration of norethindrone by 11% and increased the extent of absorption by 27% and decreased the maximum concentration of ethinyl estradiol by 30% but not the extent of absorption. Distribution Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive ( > 95%); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis. Metabolism Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation. Excretion Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of LOESTRIN 24 Fe tablets are approximately 8 hours and 14 hours, respectively. Clinical Studies In an active-controlled clinical trial, 743 women 18 to 45 years of age were studied to assess the efficacy of LOESTRIN 24 Fe, for up to six 28-day cycles. The racial demographic of women randomized to LOESTRIN 24 Fe was: 69.5% Caucasian, 15.5% African-American, 10.4% Hispanic, 2.3% Asian and 2.3% Native American/Other. Women with body mass index (BMI) greater than 35 mg/m² were excluded from the study. The weight range for those women treated was 90 to 260 pounds, with a mean weight of 147 pounds. Among the women in the study randomized to LOESTRIN 24 Fe, 38.9% had not used hormonal contraception immediately prior to enrolling in this study. A total of 583 women completed 6 cycles of treatment. There were a total of 5 on-treatment pregnancies among women aged 18 to 45 years in 3,565 treatment cycles during which no back-up contraception was used. The Pearl Index for LOESTRIN 24 Fe was 1.82 (95% confidence interval 0.59 to 4.25).

CLINICAL PHARMACOLOGY Oral Contraception Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). In vitro and animal studies have shown that norethindrone combines high progestational activity with low intrinsic androgenicity. In humans, norethindrone acetate in combination with ethinyl estradiol does not counteract estrogen-induced increases in sex hormone binding globulin (SHBG). Following multiple-dose administration of ESTROSTEP, serum< SHBG concentrations increase two- to three-fold and free testosterone concentrations decrease by 47% to 64%, indicating minimal androgenic activity. ACNE Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of norethindrone acetate and ethinyl estradiol increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. Pharmacokinetics Absorption Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are rapidly absorbed, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol. Administration of norethindrone acetate/ethinyl estradiol with a high fat meal decreases rate, but not extent, of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27% following administration with food. Plasma concentrations of norethindrone and ethinyl estradiol following chronic administration of ESTROSTEP to 17 women are shown below (Figure 1). Mean steady- state concentrations of norethindrone for the 1/20, 1/30, and 1/35 tablet strengths increased as ethinyl estradiol dose increased over the 21-day dose regimen, due to dose- dependent effects of ethinyl estradiol on serum SHBG concentrations (Table 1). Mean steady-state plasma concentrations of ethinyl estradiol for the 1/20, 1/30, and 1/35 tablet strengths were proportional to ethinyl estradiol dose (Table 1). Figure 1. Mean Steady-State Plasma Ethinyl Estradiol and Norethindrone Concentrations Following Chronic Administration of ESTROSTEP Table 1. Mean (SD) Steady-State Pharmacokinetic Parameters Following Chronic Administration of ESTROSTEPa Norethindrone Acetate/Ethinyl Estradiol Dose Cycle Day Cmax AUC CL/F SHBGb Norethindrone mg/µg ng/mL ng·hr/mL mL/min nmol/L 1/20 5 10.8 (3.9) 81.1 (28.5) 220 (137) 120 (33) 1/30 12 12.7 (4.1) 102 (32) 166 (85) 139 (42) 1/35 21 12.7 (4.1) 109 (32) 152 (73) 163 (40) Ethinyl Estradiol mg/µg pg/mL pg·hr/mL mL/min nmol/L 1/20 5 61.0 (16.8) 661 (190) 549 (171) 1/30 12 92.4 (26.9) 973 (293) 546 (199) 1/35 21 113 (44) 1149 (372) 568 (219) a Cmax = Maximum plasma concentration; AUC(0-24) = Area under the plasma concentration-time curve over the dosing interval; CL/F = Apparent oral clearance. b Mean (SD) baseline value = 55 (29) nmol/L. No age-related differences were seen in plasma concentrations of ethinyl estradiol and norethindrone following administration of ESTROSTEP to 119 postmenarchal women ages 15 to 48 years. Distribution Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive ( > 95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis. ESTROSTEP increases serum SHBG concentrations two- to three-fold (Table 1). Metabolism Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first- pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation. Excretion Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites . Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of ESTROSTEP are approximately 13 hours and 19 hours, respectively. Special Population Race The effect of race on the disposition of ESTROSTEP has not been evaluated. Renal Insufficiency The effect of renal disease on the disposition of ESTROSTEP has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function. Hepatic Insufficiency The effect of hepatic disease on the disposition of ESTROSTEP has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function. Drug-Drug Interactions Numerous drug-drug interactions have been reported for oral contraceptives. A summary of these is found under PRECAUTIONS, Drug Interactions.

TAYTULLA (norethindrone acetate and ethinyl estradiol) Capsules and Ferrous Fumarate Capsules WARNING CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke [see CONTRAINDICATIONS]. DESCRIPTION Norethindrone Acetate and Ethinyl Estradiol Capsules and Ferrous Fumarate Capsules contain norethindrone acetate, a progestin, and ethinyl estradiol, an estrogen. TAYTULLA provides an oral contraceptive regimen consisting of 24 pink active soft gelatin capsules that contain the active ingredients, followed by 4 maroon non-hormonal placebo soft gelatin capsules as specified below: 24 oval, opaque, pale pink soft gelatin capsules each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. 4 oval, opaque, maroon, capsules each containing 75 mg ferrous fumarate Each pink active capsule also contains the following inactive ingredients: sesame oil, linoleoyl polyoxylglycerides, DL-α-tocopherol, dehydrated alcohol, gelatin, sorbitol and glycerin, FD&C Red #40, and titanium dioxide. Each maroon non-hormonal placebo capsule contains ferrous fumarate, soybean oil, lecithin, yellow beeswax, gelatin, sorbitol, glycerin, FD&C Blue #1, FD&C Red #40 and titanium dioxide. The ferrous fumarate capsules do not serve any therapeutic purpose. The chemical name of ethinyl estradiol is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-]. The empirical formula of ethinyl estradiol is C20H24O2 and the structural formula is: The chemical name of norethindrone acetate is [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-]. The empirical formula of norethindrone acetate is C22H28O3 and the structural formula is:

Find Lowest Prices on LOESTRIN ® 24 Fe (norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets) WARNING CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke [see CONTRAINDICATIONS]. DESCRIPTION LOESTRIN 24 Fe is a combination oral contraceptive for oral administration consisting of active tablets containing norethindrone acetate, a progestin, and ethinyl estradiol, an estrogen, and placebo tablets containing ferrous fumarate, which serve no therapeutic purpose. Each active white tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. Inactive ingredients include acacia, lactose, magnesium stearate, starch, confectioner's sugar, and talc. Each placebo brown tablet contains 75 mg ferrous fumarate, microcrystalline cellulose, magnesium stearate, povidone, sodium starch glycolate, and compressible sugar. The ferrous fumarate tablets do not serve any therapeutic purpose. Ferrous fumarate tablets are not USP for dissolution and assay. The chemical name of ethinyl estradiol is 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17diol. The empirical formula of ethinyl estradiol is C20H24O2 and the structural formula is: The chemical name of norethindrone acetate is 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3one acetate. The empirical formula of norethindrone acetate is C22H28O3 and the structural formula is:

ESTROSTEP® 21 (norethindrone acetate and ethinyl estradiol) Tablets, USP (Each white triangular tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol; each white square tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol; each white round tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol.) Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. DESCRIPTION ESTROSTEP is a graduated estrophasic providing estrogen in a graduated sequence over a 21-day period with a constant dose of progestogen. ESTROSTEP 21 provides for a 21-day dosage regimen of oral contraceptive tablets. Each white triangle-shaped tablet contains 1 mg norethindrone acetate [(17 alpha)- 17-(acetyloxy)-19-norpregna-4-en-20-yn-3-one] and 20 mcg ethinyl estradiol [(17 alpha)- 19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol]; each white square-shaped tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol; and each white round tablet contains 1 mg norethindrone acetate, 35 mcg ethinyl estradiol. Each tablet also contains calcium stearate; lactose; microcrystalline cellulose; and starch. The structural formulas are as follows: Each ESTROSTEP 21 tablet dispenser contains five white triangular tablets, seven white square tablets, and nine white round tablets. These tablets are to be taken in the following order: one triangular tablet each day for five days, followed by one square tablet each day for seven days, and then one round tablet each day for nine days.

INDICATIONS TAYTULLA is indicated for use by females of reproductive age to prevent pregnancy [see Clinical Studies]. The efficacy of TAYTULLA in women with a body mass index (BMI) of more than 35 kg/m² has not been evaluated. DOSAGE AND ADMINISTRATION How To Take NA/EE And Fe To achieve maximum contraceptive effectiveness, TAYTULLA must be taken exactly as directed. Instruct patients to take one capsule by mouth at the same time every day. Capsules must be taken in the order directed on the blister pack. Capsules should not be skipped or taken at intervals exceeding 24 hours. For patient instructions for missed pills, see FDA-approved patient labeling. TAYTULLA may be administered without regard to meals [see CLINICAL PHARMACOLOGY]. How To Start TAYTULLA Instruct the patient to begin taking TAYTULLA 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 TAYTULLA use, instruct the patient to take one pink capsule daily, beginning on Day one (1) of her menstrual cycle (the first day of menstruation is Day one). She should take one pink capsule daily for 24 consecutive days, followed by one maroon capsule daily on days 25 through 28. TAYTULLA 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 TAYTULLA 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 TAYTULLA use, instruct the patient to take one pink capsule daily, beginning on the first Sunday after the onset of her menstrual period. She should take one pink capsules capsule daily for 24 consecutive days, followed by one maroon capsule daily on days 25 through 28. TAYTULLA should be taken in the order directed on the package at the same time each day. TAYTULLA 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 TAYTULLA on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her pink capsules on the next day after ingestion of the last maroon capsule, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of TAYTULLA is started later than the day following administration of the last maroon capsule, the patient should use another method of contraception until she has taken a pink capsule daily for 7 consecutive days. For postpartum women who do not breastfeed or after a second trimester abortion, start TAYTULLA no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts TAYTULLA 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 TAYTULLA for 7 consecutive days. TAYTULLA may be initiated immediately after a first-trimester abortion or miscarriage; if the patient starts TAYTULLA immediately, additional contraceptive measures are not needed. 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 pink capsule on the day she would have taken her next COC pill. She should not continue taking the tablet 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 TAYTULLA. If she previously used a vaginal ring or transdermal patch, she should start using TAYTULLA 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 pink capsule 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 pink capsule 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. Advice In Case Of Gastrointestinal Disturbances If the patient vomits or has diarrhea (within 3 to 4 hours after she takes a pink capsule), she should follow the instructions in the “What to Do if You Miss Capsules” section [see FDA-approved patient labeling]. HOW SUPPLIED Dosage Forms And Strengths TAYTULLA is available in blister packs. Each blister pack contains 28 soft gelatin capsules in the following order: 24 oval, opaque, pale pink (active) soft gelatin capsule with 'WC' printed on the outer shell in white and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. 4 oval, opaque, maroon, (non-hormonal placebo) capsules imprinted with “WC” on one side and each containing 75 mg ferrous fumarate. The ferrous fumarate capsules do not serve any therapeutic purpose. Storage And Handling TAYTULLA (norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules) is available in blister cards (dispensers) containing 28 soft gelatin capsules: Each blister card contains 28 capsules in the following order: 24 oval, opaque, pale pink (active) soft gelatin capsule with 'WC' printed on the outer shell in white and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. 4 oval, opaque, maroon, (non-hormonal placebo) capsules imprinted with “WC” on one side and each containing 75 mg ferrous fumarate. The ferrous fumarate capsules do not serve any therapeutic purpose. Each blister card is packed with a black wallet in a carton (NDC 0023-5862-28). Cartons of 5 blister cards packed individually in 5 cartons are provided for dispensing (NDC 0023-5862-30). 5 cartons -each carton contains 1 blister card (28): NDC 0023-5862-28 Storage Conditions Store at 25° C (77° F); excursions permitted to 15 to 30° C (59 to 86° F) [see USP Controlled Room Temperature]. Distributed by: Allergan USA, Inc. Irvine, CA 92612. Revised: Aug 2016

INDICATIONS LOESTRIN 24 Fe is indicated for use by women to prevent pregnancy [see Clinical Studies]. The efficacy of LOESTRIN 24 Fe in women with a body mass index (BMI) of > 35 kg/m² has not been evaluated. DOSAGE AND ADMINISTRATION How To Start LOESTRIN 24 Fe LOESTRIN 24 Fe is dispensed in a blister card [see HOW SUPPLIED/Storage and Handling]. LOESTRIN 24 FE may be started using either a Day 1 start or a Sunday start (see Table 1). For the first cycle of a Sunday Start regimen, an additional method of contraception must be used until after the first 7 consecutive days of administration. How To Take LOESTRIN 24 Fe Table 1: Instructions for Administration of LOESTRIN 24 Fe Starting COCs in women not currently using hormonal contraception (Day 1 Start or Sunday Start) Important: Consider the possibility of ovulation and conception prior to initiation of this product. Tablet Color: LOESTRIN 24 Fe active tablets are white (Day 1 to Day 24). LOESTRIN 24 Fe inactive tablets are brown (Day 25 to Day 28). Day 1 Start: Take first white active tablet without regard to meals on the first day of menses. Take subsequent active tablets once daily at the same time each day for a total of 21 days. Take one brown inactive tablet daily for 7 days and at the same time of day that active tablets were taken. Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last inactive tablet). Sunday Start: For each 28-day course, take in the following order: Take the white active tablet without regard to meals on the first Sunday after the onset of menses. Due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms and spermicide) for the first 7 days of the patient’s first cycle pack of LOESTRIN 24 Fe. Take subsequent active tablets once daily at the same time each day for a total of 24 days. Take one brown tablet (ferrous fumarate) daily for the following 4 days and at the same time of day that active tablets were taken. A scheduled period should occur during the 4 days that the brown tablets are taken. Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the Sunday after taking the last inactive tablet) and additional non-hormonal contraceptive is not needed. Switching to LOESTRIN 24 Fe from another oral contraceptive Start on the same day that a new pack of the previous oral contraceptive would have started. Switching from another contraceptive method to LOESTRIN 24 Fe Start LOESTRIN 24 Fe: Transdermal patch On the day when next application would have been scheduled. Vaginal ring On the day when next insertion would have been scheduled Injection On the day when next injection would have been scheduled Intrauterine contraceptive On the day of removal If the IUD is not removed on first day of the patient’s menstrual cycle, additional non-hormonal contraceptive (such as condoms and spermicide) is needed for the first seven days of the first cycle pack. Implant On the day of removal Complete instructions on proper tablet usage are located in the FDA-approved patient labeling. Starting LOESTRIN 24 Fe After Abortion Or Miscarriage First-trimester After a first-trimester abortion or miscarriage, LOESTRIN 24 Fe may be started immediately. An additional method of contraception is not needed if LOESTRIN 24 Fe is started immediately. If LOESTRIN 24 Fe is not started within 5 days after termination of the pregnancy, the patient must use additional non-hormonal contraception (such as condoms and spermicide) for the first 7 days of her first 28-day course of LOESTRIN 24 Fe. Second-trimester Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start LOESTRIN 24 Fe following the instructions in Table 1 for Sunday start. Use additional non-hormonal contraception (such as condoms and spermicide) for the first 7 days of the patient’s first 28-day course of LOESTRIN 24 Fe [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and FDA-approved Patient Labeling]. Starting LOESTRIN 24 Fe After Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with LOESTRIN 24 Fe following the instructions in Table 1 for women not currently using hormonal contraception. If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of LOESTRIN 24 Fe [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Use in Specific Populations]. Missed Tablets Table 2: Instructions for Missed LOESTRIN 24 Fe Tablets If one active tablet is missed in Weeks 1, 2 or 3 Take the tablet as soon as possible. Take the next pill at the regular time, and continue taking one tablet a day until the pack is finished. Back-up contraception is not needed If two consecutive active tablets are missed in Week 1 or Week 2 Take the two missed tablets as soon as possible and the next two active tablets the next day. Continue taking one tablet a day until the pack is finished. Additional non-hormonal contraception (such as condoms and spermicide) must be used as back-up if the patient has sex within 7 days after missing tablets. If two consecutive active tablets are missed in Week 3 or Week 4 or three or more consecutive active tablets are missed at any time Day 1 Start: Throw out the rest of the pack and start a new pack that same day. Sunday Start: Continue taking one tablet a day until Sunday, then throw out the rest of the pack and start a new pack that same day. Additional non-hormonal contraception (such as condoms and spermicide) must be used as back-up if the patient has sex within 7 days after missing 3 tablets. Advice In Case Of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures must be taken. If vomiting or diarrhea occurs within 3-4 hours after taking a white tablet, handle this as a missed tablet [see FDA-Approved Patient Labeling]. HOW SUPPLIED Dosage Forms And Strengths LOESTRIN 24 Fe (norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets) is available in blister packs. Each blister pack (28 tablets) contains in the following order: 24 white, round (active) tablets imprinted with “WC” on one side and “530” on the other and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. 4 brown, round (non-hormonal placebo) tablets imprinted with “PD 622” on one side and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose. Storage And Handling Loestrin® 24 Fe is available in blister card dispensers containing 28 tablets: NDC 0430-0530-14 Cartons of 5 blister cards (dispensers) NDC 0430-0530-60 Cartons of 30 blister cards (dispensers) Each blister card (28 tablets) contains in the following order: 24 white, round (active) tablets imprinted with “WC” on one side and “530” on the other and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. 4 brown, round (non-hormonal placebo) tablets imprinted with “PD 622” on one side and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose. Storage Conditions Store at 20° to 25°C (68°F to 77° F); excursions permitted from 15°C to 30°C (59°F to 86° F) [see USP Controlled Room Temperature]. Protect from light. Manufactured by: Warner Chilcott Company, LLC Fajardo, PR 00738. Marketed by: Warner Chilcott (US), LLC Rockaway, NJ 07866 1-800-521-8813. Revised: Aug 2016

INDICATIONS ESTROSTEP is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. ESTROSTEP is indicated for the treatment of moderate acne vulgaris in females, ≥ 15 years of age, who have no known contraindications to oral contraceptive therapy, desire oral contraception, have achieved menarche, and are unresponsive to topical antiacne medications. ESTROSTEP should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control and plans to stay on it for at least 6 months. Oral contraceptives are highly effective for pregnancy prevention. Table 2 lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates. Table 2: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States. % of Women Experiencing an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year3 Method (1) Typical Use 1 (2) Perfect Use2 (3) (4) Chance4 85 85 Spermicides5 26 6 40 Periodic Abstinence 25 63 Calendar 9 Ovulation Method 3 Symptothermal6 2 Post-ovulation 1 Cap7 Parous Women 40 26 42 Nulliparous Women 20 9 56 Sponge Parous Women 40 20 42 Nulliparous Women 20 9 56 Diaphragm7 20 6 56 Withdrawal 19 4 Condom8 Female (Reality) 21 5 56 Male 14 3 61 Pill 5 71 Progestin only 0.5 Combined 0.1 IUD Progesterone T 2.0 1.5 81 Copper T380A 0.8 0.6 78 LNg 20 0.1 0.1 81 Depo-Provera 0.3 0.3 70 Norplant and Norplant-2 0.05 0.05 88 Female Sterilization 0.5 0.5 100 Male Sterilization 0.15 0.10 100 Emergency Contraceptives Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9 Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10 Source: Trussell J, The Essentials of Contraception. In Hatcher RA, Trussell J, Stewart F, Cates W, Stweart GK, Kowel D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. 1Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 2 Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. 3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for 1 year. 4 The percentages becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. 5 Foams, creams, gels, vaginal suppositories, and vaginal film. 6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. 7 With spermicidal cream or jelly. 8 Without spermicides. 9 The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 4 light-orange pills), Lo/Ovral (1 dose is 4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills). 10 However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age. ESTROSTEP was evaluated for the treatment of acne vulgaris in two randomized, double-blind, placebo-controlled, multicenter, Phase 3, six (28 day) cycle studies. A total of 295 patients received ESTROSTEP and 296 received placebo. Mean age at enrollment for both groups was 24 years. At six months each study demonstrated a statistically significant difference between ESTROSTEP and placebo for mean change from baseline in lesion counts (see Table 3 and Figure 2). Each study also demonstrated overall treatment success in the investigator's global evaluation. Patients with severe androgen excess were not studied. Table 3. Acne Vulgaris Indication Pooled Data 376-403 and 376-404 Observed Means at Six Months and at Baseline* Intent To Treat Population ESTROSTEP® N=296 Placebo N=295 Difference in Counts Between Estrostep and Placebo at Six Months (95% CI)** Number of Lesions Counts % reduction Counts % reduction Inflammatory Lesions Baseline Mean 29 29 Sixth Month Mean 14 52% 17 41% 3 (±2 ) Non-inflammatory Baseline Mean 44 43 Sixth Month Mean 27 38% 32 25% 5 (±3.5 ) Total Lesions Baseline Mean 74 72 Sixth Month Mean 42 43% 49 32% 7 (±5) *Numbers rounded to nearest integer **Limits for 95% Confidence Interval; not adjusted for baseline differences ESTROSTEP users who started with about 74 acne lesions had about 42 lesions after 6 months of treatment. Placebo users who started with about 72 acne lesions had about 49 lesions after the same duration of treatment. Figure 2. Mean Percent Reduction in Total Lesion Counts From Baseline to Each 28-Day Cycle and Mean Total Lesion Counts at Each Cycle Following Administration of ESTROSTEP and Placebo (Statistically significant differences were not found in both studies individually until cycle 6) DOSAGE AND ADMINISTRATION The tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in either three or four rows of seven week off." Two dosage regimens are described, one of which may be more convenient or suitable than the other for an individual patient. For the initial cycle of therapy, the patient begins her tablets according to the Day-1 Start or Sunday-Start regimen. With either regimen, the patient takes one tablet daily for 21 consecutive days followed by one week of no tablets. Sunday-Start Regimen: The patient begins taking tablets from the top row on the first Sunday after menstrual flow begins. When menstrual flow begins on Sunday, the first tablet is taken on the same day. The last tablet in the dispenser will then be taken on a Saturday, followed by no tablets for a week (7 days). For all subsequent cycles, the patient then begins a new 21-tablet regimen on the eighth day, Sunday, after taking her last tablet. Following this regimen of 21 days on-7 days off, the patient will start all subsequent cycles on a Sunday. Day-1 Start Regimen: The first day of menstrual flow is Day 1. The patient places the self-adhesive day label strip that corresponds to her starting day over the preprinted days on the tablet dispenser. She starts taking one tablet daily, beginning with the first tablet in the top row. The patient completes her 21-tablet regimen when she has taken the last tablet in the tablet dispenser. She will then take no tablets for a week (7 days). For all subsequent cycles, the patient begins a new 21-tablet regimen on the eighth day after taking her last tablet, again starting with the first tablet in the top row after placing the appropriate day label strip over the preprinted days on the tablet dispenser. Following this regimen of 21 days on-7 days off, the patient will start all subsequent cycles on the same day of the week as the first course. Likewise, the interval of no tablets will always start on the same day of the week. Tablets should be taken regularly at the same time each day and can be taken without regard to meals. It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule. Special Notes on Administration Menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after discontinuing medication. If spotting occurs while on the usual regimen of one tablet daily, the patient should continue medication without interruption. If a patient forgets to take one or more white tablets, the following is suggested: One tablet is missed take tablet as soon as remembered take next tablet at the regular time Two consecutive tablets are missed (Week 1 or Week 2) take two tablets as soon as remembered take two tablets the next day use another birth control method for seven days following the missed tablets Two consecutive tablets are missed (Week 3) Sunday-Start Regimen: take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tablets Day-1 Start Regimen: discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets Three (or more) consecutive tablets are missed Sunday-Start Regimen: take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tablets Day-1 Start Regimen: discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets The possibility of ovulation occurring increases with each successive day that scheduled tablets are missed. While there is little likelihood of ovulation occurring if only one tablet is missed, the possibility of spotting or bleeding is increased. This is particularly likely to occur if two or more consecutive tablets are missed. In the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from a new tablet dispenser on the next Sunday or the first day (Day 1) depending on her regimen. Persistent bleeding which is not controlled by this method indicates the need for reexamination of the patient, at which time nonfunctional causes should be considered. Use of Oral Contraceptives in the Event of a Missed Menstrual Period If the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period and oral contraceptives should be withheld until pregnancy has been ruled out. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen. pregnancy and, when taken correctly, have a failure rate of about 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 3% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy. ESTROSTEP may also be taken to treat moderate acne in females who are at least 15 years of age, have started having menstrual periods, are able to use the pill and want the pill for birth control, plan to stay on the pill for at least 6 months, and have not improved with acne medicines that are put on the skin. For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life- threatening or may cause temporary or permanent disability. The risks associated with taking oral contraceptives increase significantly if you: Smoke Have high blood pressure, diabetes, high cholesterol Have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, or malignant or benign liver tumors. You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding. Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Most side effects of the pill are not serious. The most common side effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea, vomiting, and breakthrough bleeding, may subside within the first three months of use. The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill: Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris), or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences. Liver tumors, which may rupture and cause severe bleeding. A possible but not definite association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer. High blood pressure, although blood pressure usually returns to normal when the pill is stopped. The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your doctor or health care provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, may decrease oral contraceptive effectiveness. Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This very small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the increase in breast cancer diagnoses is caused by the pill. You should have regular breast examinations by a health care provider and examine your own breasts monthly. Tell your health care provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone-sensitive tumor. Some studies have found an increase in the incidence of precancerous lesions of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. Taking the pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus. Be sure to discuss any medical condition you may have with your health care provider. Your health care provider will take a medical and family history and examine you before prescribing oral contraceptives. The physical examination may be delayed to another time if you request it and your health care provider believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information leaflet gives you further information which you should read and discuss with your health care provider. ESTROSTEP (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. Revised June 2001. PARKE-DAVIS, Div of Warner-Lambert Co. Morris Plains, NJ 07950, USA. Direct Medical Inquiries to: Parke-Davis Warner-Lambert Company, 201 Tabor Road, Morris Plains, NJ 07950. FDA Rev date: 6/14/2002

PATIENT INFORMATION Guide for Using TAYTULLA (Norethindrone Acetate and Ethinyl Estradiol) Capsules and Ferrous Fumarate Capsules WARNING TO WOMEN WHO SMOKE Do not use TAYTULLA if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke. Birth control pills help to lower the chances of becoming pregnant when taken as directed. They do not protect against HIV infection (AIDS) and other sexually transmitted infections. What is TAYTULLA? TAYTULLA is a birth control pill. It contains two female hormones, an estrogen called ethinyl estradiol, and a progestin called norethindrone acetate. How well does TAYTULLA work? Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The better you follow the directions, the less chance you have of getting pregnant. Based on the results of one clinical study of a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets lasting six months, about 1 to 4 out of 100 women may get pregnant during the first year they use TAYTULLA. Women with a BMI above 35 kg/m² were not studied in the clinical trial, so it is not known how well TAYTULLA protects against pregnancy in such women. If you are overweight, discuss with your healthcare provider whether TAYTULLA is the best choice for you. The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant. How do I take TAYTULLA? 1. Be sure to read these directions before you start taking your capsules or anytime you are not sure what to do. 2. The right way to take the capsule is to take one capsule every day at the same time in the order directed on the package. TAYTULLA can be taken without regard to meals. If you miss capsules you could get pregnant. This includes starting the pack late. The more capsules you miss, the more likely you are to get pregnant. See “WHAT TO DO IF YOU MISS CAPSULES” below. 3. Many women have spotting or light bleeding at unexpected times, or may feel sick to their stomach during the first 1 to 3 packs of capsules. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the capsules. The problem will usually go away. If it does not go away, check with your healthcare provider. 4. Missing capsules can also cause spotting or light bleeding, even when you make up these missed capsules. On the days you take two capsules, to make up for missed capsules, you could also feel a little sick to your stomach. 5. If you have vomiting (within 3 to 4 hours after you take your capsule), you should follow the instructions for “WHAT TO DO IF YOU MISS CAPSULES.” If you have diarrhea or if you take certain medicines, including some antibiotics and some herbal products such as St. John's Wort, your capsules may not work as well. Use a back-up method (such as condoms and spermicides) until you check with your healthcare provider. 6. If you have trouble remembering to take TAYTULLA, talk to your healthcare provider about how to make capsule-taking easier or about using another method of birth control. 7. If you have any questions or are unsure about the information in this leaflet, call your healthcare provider. Before You Start Taking Your TAYTULLA 1. Decide What Time of Day You Want to Take Your Capsule. It is important to take TAYTULLA in the order directed on the package at the same time every day. TAYTULLA can be taken without regard to meals. 2. Look at Your Capsule Pack – It has 28 Capsules The TAYTULLA-pill pack has 24 “active” pink capsules (with hormones) to be taken for 24 days, followed by 4 “reminder” maroon capsules (without hormones) to be taken for the next four days. 3. Also look for: Where on the pack to start taking capsules, In what order to take the capsules (follow the arrows shown in the picture above) The week numbers as shown in the picture above. 4. Be sure you have ready at all times another kind of birth control (such as a condoms and spermicide) to use as a back-up in case you miss capsules, and an extra, full pill pack. When to Start the First Pack of Capsules You have a choice for which day to start taking your first pack of capsules. Decide with your healthcare provider which is the best day for you. Pick a time of day which will be easy to remember. Day 1 Start: Pick the day label strip that starts with the first day of your period (this is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins). Place this day label strip on the capsule dispenser over the area that has the days of the week (starting with Sunday) printed on the plastic. Take the first pink pill of the pack during the first 24 hours of your period. You will not need to use a back-up method of birth control, since you are starting the capsule at the beginning of your period. However, if you start TAYTULLA later than the first day of your period, you should use another method of birth control (such as a condom and spermicide) as a back-up method until you have taken 7 pink capsules. Sunday Start: Take the first pink capsule of the pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. Use another method of birth control (such as a condom and spermicide) as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). This also applies if you start TAYTULLA after having been pregnant, and you have not had a period since your pregnancy. When You Switch From a Different Birth Control Tablet When switching from another birth control pill, finish all the tablets, then TAYTULLA should be started on the same day that a new pack of the previous birth control tablet would have been started. When You Switch From Another Type of Birth Control Method When switching from a transdermal patch or vaginal ring, finish the 21 days of use, wait 7 days, then TAYTULLA should be started when the next application would have been due. When switching from an injection, TAYTULLA should be started when the next injection would have been due. When switching from an intrauterine device or an implant, TAYTULLA should be started on the day of removal. What to Do During the Month 1. Take one capsule at the same time every day until the pack is empty. Do not skip capsules even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). 2. Do not skip capsules even if you do not have sex very often. When you finish a pack of capsules, start the next pack on the day after your last maroon capsule. Do not wait any days between packs. What to Do if You Miss Capsules NA/EE and Fe may not be as effective if you miss any pink capsules, especially if you miss the first few or the last few pink capsules in a pack. If you miss 1 pink capsule: Take the capsule as soon as you remember. Take the next capsule at your regular time. This means you may take two capsules in one day. You do not need to use a back-up birth control method if you have sex. If you miss 2 pink capsules in a row in week 1 OR week 2 of your pack: Take two capsules on the day you remember and two capsules the next day. Then take one capsule a day until you finish the pack. You could become pregnant if you have sex in the 7 days after you restart your capsules. You must use another birth control method (such as a condom and spermicide) as a back-up for those 7 days. If you miss 2 pink capsules in a row in week 3 or week 4 of your pack: 1. If you are a Day 1 Starter: Throw out the rest of the TAYTULLA pack and start a new pack that same day. If you are a Sunday Starter: Keep taking one capsule every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack of capsules that same day. 2. You could become pregnant if you have sex in the 7 days after you restart your capsules. You must use another birth control method (such as a condom and spermicide) as a back-up for those 7 days. 3. You may not have your period this month but this is expected. However, if you miss your period two months in a row, call your healthcare provider because you might be pregnant. If you miss 3 or more pink capsules in a row during any week: 1. If you are a Day 1 Starter: Throw out the rest of the capsule pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 capsule every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack of capsules that same day. 2. You could become pregnant if you have sex on the days when you missed capsules or during the first 7 days after you restart your capsules. You must use another birth control method (such as a condom and spermicide) as a back-up the next time you have sex and for the first 7 days after you restart your capsules. 3. You may not have your period this month but this is expected. However, if you miss your period two months in a row, call your healthcare provider because you might be pregnant. If you miss any of the 4 maroon capsules in Week 4: Throw away the capsules you missed. Keep taking one capsule each day until the pack is empty. You do not need a back-up method. Start the next pack of TAYTULLA as scheduled. Finally, if you are still not sure what to do about the capsules you have missed: Use a back-up method (such as a condom and spermicide) anytime you have sex. Contact your healthcare provider and continue taking one active pink capsule each day until otherwise directed. Who should not take TAYTULLA? Your healthcare provider will not give you TAYTULLA if you have: Ever had blood clots in your arms, legs (deep vein thrombosis), lungs (pulmonary embolism), or eyes (retinal thrombosis) Ever had a stroke Ever had a heart attack Certain heart valve problems or heart rhythm abnormalities that can cause blood clots to form in the heart An inherited problem with your blood that makes it clot more than normal High blood pressure that medicine cannot control Diabetes with kidney, eye, nerve, or blood vessel damage Ever had certain kinds of severe migraine headaches with aura, numbness, weakness or changes in vision, or have any migraine headaches if you are over age 35 Ever had breast cancer or any cancer that is sensitive to female hormones Liver disease, including liver tumors Also, do not take birth control pills if you: Smoke and are over 35 years old Are or suspect you are pregnant Have any unexplained bleeding from the vagina Birth control pills may not be a good choice for you if you have ever had jaundice (yellowing of the skin or eyes) caused by pregnancy, also called cholestasis of pregnancy. Tell your healthcare provider if you have ever had any of the above conditions (your healthcare provider may recommend another method of birth control). What else should I know about taking TAYTULLA? Birth control pills do not protect you against any sexually transmitted infection, including HIV, the virus that causes AIDS. Do not skip any pills, even if you do not have sex often. If you miss a period, you could be pregnant. However, some women miss periods or have light periods on birth control pills, even when they are not pregnant. Contact your healthcare provider for advice if you: Think you are pregnant Miss one period and have not taken your birth control pills every day Miss two periods in a row Birth control pills should not be taken during pregnancy. However, birth control pills taken by accident during pregnancy are not known to cause birth defects. You should stop TAYTULLA at least four weeks before you have surgery and not restart it until at least two weeks after the surgery, due to an increased risk of blood clots. If you are breastfeeding, consider another birth control method until you are ready to stop breastfeeding. Birth control pills that contain estrogen, like TAYTULLA, may decrease the amount of milk you make. A small amount of the pill's hormones pass into breast milk. Tell your healthcare provider about all medicines and herbal products that you take. Some medicines and herbal products may make birth control pills less effective, including: barbiturates bosentan carbamazepine felbamate griseofulvin oxcarbazepine phenytoin rifampin St. John's wort topiramate Use a back-up or alternative birth control method when you take medicines that may make birth control pills less effective. Birth control pills may interact with lamotrigine, an anticonvulsant used for epilepsy. This may increase the risk of seizures, so your healthcare provider may need to adjust the dose of lamotrigine. If you have vomiting or diarrhea, your birth control pills may not work as well. Use another birth control method, like a condom and spermicide, until you check with your healthcare provider. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone. If you are scheduled for any laboratory tests, tell your healthcare provider that you are taking birth control pills. Certain blood tests may be affected by birth control pills. What are the most serious risks of taking TAYTULLA? Like pregnancy, birth control pills increase the risk of serious blood clots, especially in women who have other risk factors, such as smoking, obesity, or age greater than 35. This increased risk is highest when you first start taking birth control pills and when you restart the same or different birth control pills after not using them for a month or more. It is possible to die from a problem caused by a blood clot, such as a heart attack or a stroke. Some examples of serious blood clots are blood clots in the: Legs (deep vein thrombosis) Lungs (pulmonary embolus) Eyes (loss of eyesight) Heart (heart attack) Brain (stroke) Women who take birth control pills may get: High blood pressure Gallbladder problems Rare cancerous or noncancerous liver tumors All of these events are uncommon in healthy women. Call your healthcare provider right away if you have: Persistent leg pain Sudden shortness of breath Sudden blindness, partial or complete Severe pain or pressure in your chest Sudden, severe headache unlike your usual headaches Weakness or numbness in an arm or leg, or trouble speaking Yellowing of the skin or eyeballs What are the common side effects of birth control pills? The most common side effects of birth control pills are: Spotting or bleeding between menstrual periods Nausea Breast tenderness Headache These side effects are usually mild and usually disappear with time. Less common side effects are: Acne Less sexual desire Bloating or fluid retention Blotchy darkening of the skin, especially on the face High blood sugar, especially in women who already have diabetes High fat (cholesterol, triglyceride) levels in the blood Depression, especially if you have had depression in the past. Call your healthcare provider immediately if you have any thoughts of harming yourself Problems tolerating contact lenses Weight gain This is not a complete list of possible side effects. Talk to your healthcare provider if you develop any side effects that concern you. You may report side effects to the FDA at 1-800-FDA-1088. No serious problems have been reported from a birth control pill overdose, even when accidentally taken by children. Do birth control pills cause cancer? Birth control pills do not seem to cause breast cancer. However, if you have breast cancer now, or have had it in the past, do not use birth control pills because some breast cancers are sensitive to hormones. Women who use birth control pills may have a slightly higher chance of getting cervical cancer. However, this may be due to other reasons such as having more sexual partners. What should I know about my period when taking TAYTULLA? Irregular vaginal bleeding or spotting may occur while you are taking TAYTULLA. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding, which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle, is unusually heavy, or lasts for more than a few days, call your healthcare provider. Some women may not have a menstrual period but this should not be cause for alarm as long has you have taken the pills according to direction. What if I miss my scheduled period when taking TAYTULLA? It is not uncommon to miss your period. However, if you go two or more months in a row without a period, or you miss your period after a month where you did not take all your pills correctly, call your healthcare provider because you may be pregnant. Also notify your healthcare provider if you have symptoms of pregnancy such as morning sickness or unusual breast tenderness. Stop taking TAYTULLA if you are pregnant. What if I want to become pregnant? You may stop taking the capsule whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the capsule. General Advice about TAYTULLA Your healthcare provider prescribed NA/EE and Fe for you. Please do not share TAYTULLA with anyone else. Keep TAYTULLA out of the reach of children. If you have concerns or questions, ask your healthcare provider. You may also ask your pharmacist for a more detailed label written for healthcare professionals. This Patient Information has been approved by the U.S. Food and Drug Administration.

PATIENT INFORMATION LOESTRIN 24 FE (Low-ess-trinh 24 FE) (norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate) tablets What is the most important information I should know about LOESTRIN 24 Fe? Do not use LOESTRIN 24 Fe if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from hormonal birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke. What is LOESTRIN 24 Fe? LOESTRIN 24 Fe is a birth control pill (hormonal contraceptive) used by women to prevent pregnancy. How does LOESTRIN 24 FE work for contraception? Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The better you follow the directions, the less chance you have of getting pregnant. Based on the results from the clinical study, about 1 to 4 out of 100 women may get pregnant during the first year they use LOESTRIN 24 Fe. The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant. Who should not take LOESTRIN 24 Fe? Do not take LOESTRIN 24 Fe if you: smoke and are over 35 years of age had blood clots in your arms, legs, lungs, or eyes had a problem with your blood that makes it clot more than normal have certain heart valve problems or irregular heart beat that increases your risk of having blood clots had a stroke had a heart attack have high blood pressure that cannot be controlled by medicine have diabetes with kidney, eye, nerve, or blood vessel damage have certain kinds of severe migraine headaches with aura, numbness, weakness or changes in vision, or any migraine headaches if you are over 35 years of age have liver problems, including liver tumors have any unexplained vaginal bleeding are pregnant had breast cancer or any cancer that is sensitive to female hormones If any of these conditions happen while you are taking LOESTRIN 24 Fe, stop taking LOESTRIN 24 Fe right away and talk to your healthcare provider. Use non-hormonal contraception (such as condoms and spermicide) when you stop taking LOESTRIN 24 Fe. What should I tell my healthcare provider before taking LOESTRIN 24 Fe? Tell your healthcare provider if you: are pregnant or think you may be pregnant are depressed now or have been depressed in the past had yellowing of your skin or eyes (jaundice) caused by pregnancy (cholestasis of pregnancy) are breastfeeding or plan to breastfeed. LOESTRIN 24 Fe may decrease the amount of breast milk you make. A small amount of the hormones in LOESTRIN 24 Fe may pass into your breast milk. Talk to your healthcare provider about the best birth control method for you while breastfeeding. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. LOESTRIN 24 FE may affect the way other medicines work, and other medicines may affect how well LOESTRIN 24 Fe works. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take LOESTRIN 24 Fe? Read the Instructions for Use at the end of this Patient Information. What are the possible serious side effects of LOESTRIN 24 Fe? Like pregnancy, LOESTRIN 24 Fe may cause serious side effects, including blood clots in your lungs, heart attack, or a stroke that may lead to death. Some other examples of serious blood clots include blood clots in the legs or eyes. Serious blood clots can happen especially if you smoke, are obese, or are older than 35 years of age. Serious blood clots are more likely to happen when you: first start taking birth control pills restart the same or different birth control pills after not using them for a month or more Call your healthcare provider or go to a hospital emergency room right away if you have: leg pain that will not go away a sudden, severe headache unlike your usual headaches sudden severe shortness of breath weakness or numbness in your sudden change in vision or arm or leg blindness trouble speaking chest pain Other serious side effects include: liver problems, including: rare liver tumors jaundice (cholestasis), especially if you previously had cholestasis of pregnancy. Call your healthcare provider if you have yellowing of your skin or eyes. high blood pressure. You should see your healthcare provider for a yearly check of your blood pressure. gallbladder problems changes in the sugar and fat (cholesterol and triglycerides) levels in your blood new or worsening headaches including migraine headaches depression possible cancer in your breast and cervix swelling of your skin especially around your mouth, eyes, and in your throat (angioedema). Call your healthcare provider if you have a swollen face, lips, mouth tongue or throat, which may lead to difficulty swallowing or breathing. Your chance of having angioedema is higher is you have a history of angioedema. dark patches of skin around your forehead, nose, cheeks and around your mouth, especially during pregnancy (chloasma). Women who tend to get chloasma should avoid spending a long time in sunlight, tanning booths, and under sun lamps while taking LOESTRIN 24 Fe. Use sunscreen if you have to be in the sunlight. What are the most common side effects of LOESTRIN 24 Fe? headache vaginal infections nausea menstrual cramps breast tenderness mood changes acne weight gain These are not all the possible side effects of LOESTRIN 24 Fe. For more information, ask your healthcare provider or pharmacist. You may report side effects to the FDA at 1-800-FDA-1088. What else should I know about taking LOESTRIN 24 Fe? If you are scheduled for any lab tests, tell your healthcare provider you are taking LOESTRIN 24 Fe. Certain blood tests may be affected by LOESTRIN 24 Fe. LOESTRIN 24 Fe does not protect against HIV infection (AIDS) and other sexually transmitted infections. How should I store LOESTRIN 24 Fe? Store LOESTRIN 24 Fe at room temperature between 68°F to 77°F (20°C to 25°C). Store away from light. Keep LOESTRIN 24 Fe and all medicines out of the reach of children. General information about the safe and effective use of LOESTRIN 24 Fe. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LOESTRIN 24 Fe for a condition for which it was not prescribed. Do not give LOESTRIN 24 Fe to other people. This Patient Information summarizes the most important information about LOESTRIN 24 Fe. You can ask your pharmacist or healthcare provider for information about LOESTRIN 24 Fe that is written for health professionals. For more information, call Warner Chilcott at 1-800-521-8813. Do birth control pills cause cancer? Birth control pills do not seem to cause breast cancer. However, if you have breast cancer now, or have had it in the past, do not use birth control pills because some breast cancers are sensitive to hormones. Women who use birth control pills may have a slightly higher chance of getting cervical cancer. However, this may be due to other reasons such as having more sexual partners. What if I want to become pregnant? You may stop taking the pill whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the pill. What should I know about my period when taking LOESTRIN 24 Fe? Your periods may be lighter and shorter than usual. Some women may miss a period. Irregular vaginal bleeding or spotting may happen while you are taking LOESTRIN 24 Fe, especially during the first few months of use. This usually is not a serious problem. It is important to continue taking your pills on a regular schedule to prevent a pregnancy. What are the ingredients in LOESTRIN 24 Fe? Active ingredients: White pills: norethindrone acetate and ethinyl estradiol Inactive ingredients: Brown pills: ferrous fumarate INSTRUCTIONS FOR USE LOESTRIN 24 FE (Low-ess-trinh 24 FE) (norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate) tablets Important Information about taking LOESTRIN 24 Fe Take 1 pill every day at the same time. Take the pills in the order directed on your pill dispenser. Do not skip your pills, even if you do not have sex often. If you miss pills (including starting the pack late), you could get pregnant. The more pills you miss, the more likely you are to get pregnant. If you have trouble remembering to take LOESTRIN 24 Fe, talk to your healthcare provider. When you first start taking LOESTRIN 24 Fe, spotting or light bleeding in between your periods may occur. Contact your healthcare provider if this does not go away after a few months. You may feel sick to your stomach (nauseous), especially during the first few months of taking LOESTRIN 24 Fe. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If your nausea does not go away, call your healthcare provider. Missing pills can also cause spotting or light bleeding, even when you take the missed pills later. On the days you take 2 pills to make up for missed pills (see What should I do if I miss any LOESTRIN 24 Fe pills? below), you could also feel a little sick to your stomach. It is not uncommon to miss a period. However, if you miss a period and have not taken LOESTRIN 24 Fe according to directions, or miss 2 periods in a row, or feel like you may be pregnant, call your healthcare provider. If you have a positive pregnancy test, you should stop taking LOESTRIN 24 Fe. If you have vomiting or diarrhea within 3-4 hours of taking a white active pill, take another white pill from your extra pill dispenser. If you do not have an extra pill dispenser, take the next white pill in your pill dispenser. Continue taking all your remaining pills in order. Start the first pill of your next pill dispenser the day after finishing your current pill dispenser. This will be 1 day earlier than originally scheduled. Continue on your new schedule. If you have vomiting or diarrhea for more than 1 day, your birth control pills may not work as well. Use an additional birth control method, like condoms and a spermicide, until you check with your healthcare provider. Stop taking LOESTRIN 24 Fe at least 4 weeks before you have major surgery and do not restart after the surgery without asking your healthcare provider. Be sure to use other forms of contraception (like condoms and spermicide) during this time period. Before you start taking LOESTRIN 24 Fe: Decide what time of day you want to take your pill. It is important to take it at the same time every day and in the order as directed on your pill dispenser. Have backup contraception (condoms and spermicide) available and if possible, an extra full pack of pills as needed. When should I start taking LOESTRIN 24 Fe? If you start taking LOESTRIN 24 Fe and you have not used a hormonal birth control method before: There are 2 ways to start taking your birth control pills. You can either start on a Sunday (Sunday Start) or on the first day (Day 1) of your natural menstrual period (Day 1 Start). Your healthcare provider should tell you when to start taking your birth control pill. If you use the Sunday Start, use non-hormonal back-up contraception such as condoms and spermicide for the first 7 days that you take LOESTRIN 24 Fe. You do not need back-up contraception if you use the Day 1 Start. If you start taking LOESTRIN 24 Fe and you are switching from another birth control pill: Start your new LOESTRIN 24 Fe pack on the same day that you would start the next pack of your previous birth control method. Do not continue taking the pills from your previous birth control pack. If you start taking LOESTRIN 24 Fe and previously used a vaginal ring or transdermal patch: Start using LOESTRIN 24 Fe on the day you would have reapplied the next ring or patch. If you start taking LOESTRIN 24 Fe and you are switching from a progestin-only method such as an implant or injection: Start taking LOESTRIN 24 Fe on the day of removal of your implant or on the day when you would have had your next injection. If you start taking LOESTRIN 24 Fe and you are switching from an intrauterine device or system (IUD or IUS): Start taking LOESTRIN 24 Fe on the day of removal of your IUD or IUS. You do not need back-up contraception if your IUD or IUS is removed on the first day (Day 1) of your period. If your IUD or IUS is removed on any other day, use non-hormonal back-up contraception such as condoms and spermicide for the first 7 days that you take LOESTRIN 24 Fe. Keep a calendar to track your period: If this is the first time you are taking birth control pills, read, “When should I start taking LOESTRIN 24 Fe?” above. Follow these instructions for either a Sunday Start or a Day 1 Start. Sunday Start: You will use a Sunday Start if your healthcare provider told you to take your first pill on a Sunday. Take pill 1 on the Sunday after your period starts. If your period starts on a Sunday, take pill “1” that day and refer to Day 1 Start instructions below. Take 1 pill every day in the order on the pill dispenser at the same time each day for 28 days. After taking the last pill on Day 28 from the pill dispenser, start taking the first pill from a new pack, on the same day of the week as the first pack (Sunday). Take the first pill in the new pack whether or not you are having your period. Use non-hormonal back-up contraception such as condoms and spermicide for the first 7 days of the first cycle that you take LOESTRIN 24 FE. Day 1 Start: You will use a Day 1 Start if your doctor told you to take your first pill (Day 1) on the first day of your period. Take 1 pill every day in the order of the pill dispenser dial pack, at the same time each day, for 28 days. After taking the last pill on Day 28 from the pill dispenser, start taking the first pill from a new pack, on the same day of the week as the first pack. Take the first pill in the new pack whether or not you are having your period. Instructions for using your pill pack: The LOESTRIN 24 Fe pill pack has 24 “active” white pills (with hormones) to be taken for 24 days, followed by 4 “reminder” brown pills (without hormones) to be taken for the next 4 days. Figure A Look for: Where on the pack to start taking pills In what order to take the pills. Follow the arrows shown in Figure A. The week numbers as shown in Figure A. What if should I do if I miss any LOESTRIN 24 FE white pills? If you miss 1 white pill in Weeks 1, 2, or 3, follow these steps: Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. Then continue taking 1 pill every day until you finish the pack. You do not need to use a back-up birth control method if you have sex. If you miss 2 white pills in a row in Week 1 or Week 2 of your pack, follow these steps: Take the 2 missed pills as soon as possible and the next 2 pills the next day. Then continue to take 1 pill every day until you finish the pack. Use a non-hormonal birth control method (such as a condom and spermicide) as a back-up if you have sex during the first 7 days after missing your pills. If you miss 2 white pills in a row in Week 3 or Week 4, or you miss 3 or more white pills in a row at any time, follow these steps: If you are a Day 1 Starter: Throw out the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack of pills that same day. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare provider because you might be pregnant. You could become pregnant if you have sex during the first 7 days after you restart your pills. You MUST use a non-hormonal birth control method (such as a condom and spermicide) as a back-up if you have sex during the first 7 days after you restart your pills. If you miss any of the 4 brown “reminder” pills in Week 4, throw away the pills you missed and keep taking 1 pill each day until the pack is empty. You do not need to use a back-up method of birth control. If you have any questions or are unsure about the information in this leaflet, call your healthcare provider.

PATIENT INFORMATION TABLET DISPENSER The ESTROSTEP tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in either three or four rows of seven tablets each with the days of the week appearing above the first row of tablets. If your TABLET DISPENSER contains: You are taking: 21 white tablets ESTROSTEP 21 21 white tablets and 7 brown tablets ESTROSTEP Fe Each triangle tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. Each square tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol. Each round tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol. Each brown tablet contains 75 mg ferrous fumarate and is intended to help you remember to take the tablets correctly. These brown tablets are not intended to have any health benefit. DIRECTIONS To remove a tablet, press down on it with your thumb or finger. The tablet will drop through the back of the tablet dispenser. Do not press with your thumbnail, fingernail, or any other sharp object. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH, DURING THE FIRST 1-3 PACKS OF PILLS. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn't go away, check with your doctor or clinic. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use a back-up birth control method (such as condoms or spermicide) until you check with your doctor or clinic. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic. BEFORE YOU START TAKING YOUR PILLS DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. LOOK AT YOUR PILL PACK TO SEE IF IT HAS 21 OR 28 PILLS: The 21-pill pack has 21 "active" white pills (with hormones) to take for 3 weeks, followed by 1 week without pills. The 28-pill pack has 21 "active" white pills (with hormones) to take for 3 weeks, followed by 1 week of reminder brown pills (without hormones). ALSO FIND: where on the pack to start taking pills, in what order to take the pills (follow the arrows), and the week numbers as shown in the following pictures: Each ESTROSTEP 21 (norethindrone acetate and ethinyl estradiol) tablet dispenser contains five white triangular tablets, seven white square tablets, and nine white round tablets. These tablets are to be taken in the following order: one triangular tablet each day for five days, followed by one square tablet each day for seven days, and then one round tablet each day for nine days. ESTROSTEP 21 (norethindrone acetate and ethinyl estradiol) will contain: ALL WHITE PILLS 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a back-up in case you miss pills. An EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember. DAY-1 START: Pick the day label strip that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.) Place this day label strip on the tablet dispenser over the area that has the days of the week (starting with Sunday) printed on the plastic. Take the first "active" white pill of the first pack during the first 24 hours of your period. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: Take the first "active" white pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or spermicide are good back-up methods of birth control. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: 21 pills: Wait 7 days to start the next pack. You will probably have your period during that week. Be sure that no more than 7 days pass between 21-day packs. WHAT TO DO IF YOU MISS PILLS If you MISS 1 white "active" pill: Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white "active" pills in a row in Week 1 OR Week 2 of your pack: Take 2 pills on the day you remember and 2 pills the next day. Then take 1 pill a day until you finish the pack. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white "active" pill every day for 7 days. If you MISS 2 white "active" pills in a row in THE 3rd WEEK: If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white "active" pill every day for 7 days. If you MISS 3 OR MORE white "active" pills in a row (during the first 3 weeks): If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white "active" pill every day for 7 days. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE WHITE "ACTIVE" PILL EACH DAY until you can reach your doctor or clinic. Based on his or her assessment of your medical needs, your doctor or health care provider has prescribed this drug for you. Do not give this drug to anyone else. Keep this and all drugs out of the reach of children. Storage-Do not store above 25°C (77°F). Protect from light. Store tablets inside pouch when not in use. DETAILED PATIENT PACKAGE INSERT ESTROSTEP (like all oral contraceptives) are intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases. What You Should Know About Oral Contraceptives Any woman who considers using oral contraceptives (the "birth control pill" or "the pill") should understand the benefits and risks of using this form of birth control. This leaflet will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this leaflet is not a replacement for a careful discussion between you and your health care provider. You should discuss the information provided in this leaflet with him or her, both when you first start taking the pill and during your revisits. You should also follow your health care provider's advice with regard to regular check-ups while you are on the pill. EFFECTIVENESS OF ORAL CONTRACEPTIVES Oral contraceptives or "birth control pills'' or "the pill'' are used to prevent pregnancy and are more effective than other nonsurgical methods of birth control. When they are taken correctly, the chance of becoming pregnant is less than 1% (1 pregnancy per 100 women per year of use) when used perfectly, without missing any pills. Typical failure rates are actually 5% per year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle. In comparison, typical failure rates for other methods of birth control during the first year of use are as follows: Implant: < 1% Injection: < 1% IUD: < 1 to 2% Diaphragm with spermicides: 20% Spermicides alone: 26% Vaginal Sponge: 20 to 40% Female sterilization: < 1% Male sterilization: < 1% Cervical Cap: 20 to 40% Condom alone (male): 14% Condom alone (female): 21% Periodic abstinence: 25% Withdrawal: 19% No method: 85% ESTROSTEP may also be taken to treat moderate acne if all of the following are true: Your doctor says it is safe for you to use the pill You are at least 15 years old You have started having menstrual periods You want to use the pill for birth control You plan to stay on the pill for at least 6 months Your acne has not improved with acne medicines that you put on your skin. ESTROSTEP users who started with about 74 acne pimples had about 42 pimples after 6 months of treatment. Placebo users who started with about 72 acne pimples had about 49 pimples after six months of treatment. Use ESTROSTEP to treat acne only if you want the pill for birth control and plan to stay on it for at least 6 months. WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not to smoke. Some women should not use the pill. For example, you should not take the pill if you are pregnant or think you may be pregnant. You should also not use the pill if you have any of the following conditions: A history of heart attack or stroke Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes A history of blood clots in the deep veins of your legs Chest pain (angina pectoris) Known or suspected breast cancer or cancer of the lining of the uterus, cervix, or vagina Unexplained vaginal bleeding (until a diagnosis is reached by your doctor) Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill Liver tumor (benign or cancerous) Known or suspected pregnancy Tell your health care provider if you have ever had any of these conditions. Your health care provider can recommend a safer method of birth control. OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES Tell your health care provider if you have: Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram Diabetes Elevated cholesterol or triglycerides High blood pressure Migraine or other headaches or epilepsy Mental depression Gallbladder, heart, or kidney disease History of scanty or irregular menstrual periods Women with any of these conditions should be checked often by their health care provider if they choose to use oral contraceptives. Also, be sure to inform your doctor or health care provider if you smoke or are on any medications. RISKS OF TAKING ORAL CONTRACEPTIVES 1. Risk of Developing Blood Clots Blood clots and blockage of blood vessels are the most serious side effects of taking oral contraceptives; in particular, a clot in the leg can cause thrombophlebitis, and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness, or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your doctor about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breast feeding. If you are breast feeding, you should wait until you have weaned your child before using the pill. (See also the section on Breast Feeding in GENERAL PRECAUTIONS.) 2. Heart Attacks and Strokes Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or disability. Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease. 3. Gallbladder Disease Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens. 4. Liver Tumors In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, a possible but not definite association has been found with the pill and liver cancers in two studies, in which a few women who developed these very rare cancers were found to have used oral contraceptives for long periods. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer. 5. Cancer of the Reproductive Organs and Breasts Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This very small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the increase in breast cancer diagnosis is caused by the pill. You should have regular breast examinations by a health care provider and examine your own breasts monthly. Tell your health care provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone-sensitive tumor. Some studies have found an increase in the incidence of precancerous lesions of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table. Annual Number of Birth-Related or Method-Related Deaths Associated With Control of Fertility Per 100,000 Nonsterile Women by Fertility Control Method According to Age Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44 No fertility control methods* 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker** 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker** 2.2 3.4 6.6 13.5 51.1 117.2 IUD** 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 * Deaths are birth related. ** Deaths are method related. In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group. The suggestion that women over 40 who don't smoke should not take oral contraceptives is based on information from older higher dose pills and on less selective use of pills than is practiced today. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. However, all women, especially older women, are cautioned to use the lowest dose pill that is effective. WARNING SIGNALS If any of these adverse effects occur while you are taking oral contraceptives, call your doctor immediately: Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung) Pain in the calf (indicating a possible clot in the leg) Crushing chest pain or heaviness in the chest (indicating a possible heart attack) Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke) Sudden partial or complete loss of vision (indicating a possible clot in the eye) Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor or health care provider to show you how to examine your breasts) Severe pain or tenderness in the stomach area (indicating a possible ruptured liver tumor) Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression) Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems) SIDE EFFECTS OF ORAL CONTRACEPTIVES 1. Vaginal Bleeding Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your doctor or health care provider. 2. Contact Lenses If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your doctor or health care provider. 3. Fluid Retention Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your doctor or health care provider. 4. Melasma A spotty darkening of the skin is possible, particularly of the face. 5. Other Side Effects Other side effects may include change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, and vaginal infections. If any of these side effects bother you, call your doctor or health care provider. GENERAL PRECAUTIONS 1. Missed Periods and Use of Oral Contraceptives Before or During Early Pregnancy There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your health care provider before doing so. If you have not taken the pills daily as instructed and missed a menstrual period, or if you missed two consecutive menstrual periods, you may be pregnant. Check with your health care provider immediately to determine whether you are pregnant. Do not continue to take oral contraceptives until you are sure you are not pregnant, but continue to use another method of contraception. There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects, but these studies have not been confirmed. Nevertheless, oral contraceptives or any other drugs should not be used during pregnancy unless clearly necessary and prescribed by your doctor. You should check with your doctor about risks to your unborn child of any medication taken during pregnancy. 2. While Breast Feeding If you are breast feeding, consult your doctor before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, oral contraceptives may decrease the amount and quality of your milk. If possible, do not use oral contraceptives while breast feeding. You should use another method of contraception since breast feeding provides only partial protection from becoming pregnant, and this partial protection decreases significantly as you breast feed for longer periods of time. You should consider starting oral contraceptives only after you have weaned your child completely. 3. Laboratory Tests If you are scheduled for any laboratory tests, tell your doctor you are taking birth control pills. Certain blood tests may be affected by birth control pills. 4. Drug Interactions Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs include rifampin; drugs used for epilepsy such as barbiturates (for example, phenobarbital), carbamazepine, and phenytoin (Dilantin® is one brand of this drug); phenylbutazone; and possibly St. John's Wort and certain antibiotics. You may need to use additional contraception when you take drugs which can make oral contraceptives less effective. Birth control pills interact with certain drugs. These drugs include acetaminophen, clofibric acid, cyclosporine, morphine, prednisolone, salicylic acid, temazepam, and theophylline. You should tell your doctor if you are taking any of these medications. 5. Sexually Transmitted Diseases ESTROSTEP (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. INSTRUCTIONS TO PATIENT TABLET DISPENSER The ESTROSTEP tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged in either three or four rows of seven tablets each with the days of the week appearing above the first row of tablets. If your TABLET DISPENSER contains: You are taking: 21 white tablets ESTROSTEP 21 21 white tablets and 7 brown tablets ESTROSTEP Fe Each triangle tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. Each square tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol. Each round tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol. Each brown tablet contains 75 mg ferrous fumarate and is intended to help you remember to take the tablets correctly. These brown tablets are not intended to have any health benefit. DIRECTIONS To remove a tablet, press down on it with your thumb or finger. The tablet will drop through the back of the tablet dispenser. Do not press with your thumbnail, fingernail, or any other sharp object. HOW TO TAKE THE PILL IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING YOUR PILLS: BE SURE TO READ THESE DIRECTIONS: Before you start taking your pills. Anytime you are not sure what to do. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME. If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH, DURING THE FIRST 1-3 PACKS OF PILLS. If you do have spotting or light bleeding or feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn't go away, check with your doctor or clinic. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME MEDICINES, including some antibiotics, your birth control pills may not work as well. Use a back-up birth control method (such as condoms or spermicide) until you check with your doctor or clinic. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic about how to make pill-taking easier or about using another method of birth control. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your doctor or clinic. BEFORE YOU START TAKING YOUR PILLS DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL. It is important to take it at about the same time every day. LOOK AT YOUR PILL PACK TO SEE IF IT HAS 21 OR 28 PILLS: The 21-pill pack has 21 "active" white pills (with hormones) to take for 3 weeks, followed by 1 week without pills. The 28-pill pack has 21 "active" white pills (with hormones) to take for 3 weeks, followed by 1 week of reminder brown pills (without hormones). ALSO FIND: where on the pack to start taking pills, in what order to take the pills (follow the arrows), and the week numbers as shown in the following pictures: Each ESTROSTEP 21 (norethindrone acetate and ethinyl estradiol) tablet dispenser contains five white triangular tablets, seven white square tablets, and nine white round tablets. These tablets are to be taken in the following order: one triangular tablet each day for five days, followed by one square tablet each day for seven days, and then one round tablet each day for nine days. ESTROSTEP 21 (norethindrone acetate and ethinyl estradiol) will contain: ALL WHITE PILLS 4. BE SURE YOU HAVE READY AT ALL TIMES: ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a back-up in case you miss pills. An EXTRA, FULL PILL PACK. WHEN TO START THE FIRST PACK OF PILLS You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic which is the best day for you. Pick a time of day which will be easy to remember. DAY-1 START: Pick the day label strip that starts with the first day of your period. (This is the day you start bleeding or spotting, even if it is almost midnight when the bleeding begins.) Place this day label strip on the tablet dispenser over the area that has the days of the week (starting with Sunday) printed on the plastic. Take the first "active" white pill of the first pack during the first 24 hours of your period. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: Take the first "active" white pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. Use another method of birth control as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). Condoms or spermicide are good back-up methods of birth control. WHAT TO DO DURING THE MONTH 1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY. Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. 2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS: 21 pills: Wait 7 days to start the next pack. You will probably have your period during that week. Be sure that no more than 7 days pass between 21-day packs. WHAT TO DO IF YOU MISS PILLS If you MISS 1 white "active" pill: Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. You do not need to use a back-up birth control method if you have sex. If you MISS 2 white "active" pills in a row in Week 1 OR Week 2 of your pack: Take 2 pills on the day you remember and 2 pills the next day. Then take 1 pill a day until you finish the pack. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white "active" pill every day for 7 days. If you MISS 2 white "active" pills in a row in THE 3rd WEEK: 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white "active" pill every day for 7 days. If you MISS 3 OR MORE white "active" pills in a row (during the first 3 weeks): 1. If you are a Day-1 Starter: THROW OUT the rest of the pill pack and start a new pack that same day. If you are a Sunday Starter: Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. You may not have your period this month, but this is expected. However, if you miss your period 2 months in a row, call your doctor or clinic because you might be pregnant. You COULD GET PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as condoms or spermicide) as a back-up method of birth control until you have taken a white "active" pill every day for 7 days. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE WHITE "ACTIVE" PILL EACH DAY until you can reach your doctor or clinic. PREGNANCY DUE TO PILL FAILURE The incidence of pill failure resulting in pregnancy is approximately 1% (ie, one pregnancy per 100 women per year) if taken every day as directed, but more typical failure rates are about 5%. If failure does occur, the risk to the fetus is minimal. PREGNANCY AFTER STOPPING THE PILL There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy. There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. OVERDOSAGE Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your health care provider or pharmacist. OTHER INFORMATION Your health care provider will take a medical and family history and examine you before prescribing oral contraceptives. The physical examination may be delayed to another time if you request it and your health care provider believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your health care provider if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your health care provider, because this is a time to determine if there are early signs of side effects of oral contraceptive use. Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills. HEALTH BENEFITS FROM ORAL CONTRACEPTIVES In addition to preventing pregnancy, use of oral contraceptives may provide certain benefits. They are: Menstrual cycles may become more regular. Blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur. Pain or other symptoms during menstruation may be encountered less frequently. Ectopic (tubal) pregnancy may occur less frequently. Noncancerous cysts or lumps in the breast may occur less frequently. Acute pelvic inflammatory disease may occur less frequently. Oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus. If you want more information about birth control pills, ask your doctor or pharmacist. They have a more technical leaflet called the "Physician Insert," which you may wish to read. Remembering to take tablets according to schedule is stressed because of its importance in providing you the greatest degree of protection. MISSED MENSTRUAL PERIODS FOR BOTH DOSAGE REGIMENS At times there may be no menstrual period after a cycle of pills. Therefore, if you miss one menstrual period but have taken the pills exactly as you were supposed to, continue as usual into the next cycle. If you have not taken the pills correctly and miss a menstrual period, you may be pregnant and should stop taking oral contraceptives until your doctor or health care provider determines whether or not you are pregnant. Until you can get to your doctor or health care provider, use another form of contraception. If two consecutive menstrual periods are missed, you should stop taking pills until it is determined whether or not you are pregnant. Although there does not appear to be any increase in birth defects in newborn babies, if you become pregnant while using oral contraceptives, you should discuss the situation with your doctor or health care provider. Periodic Examination Your doctor or health care provider will take a complete medical and family history before prescribing oral contraceptives. At that time and about once a year thereafter, he or she will generally examine your blood pressure, breasts, abdomen, and pelvic organs (including a Papanicolaou smear, ie, test for cancer). Keep this and all drugs out of the reach of children. Storage: Do not store above 25°C (77°F). Protect from light. Store tablets inside pouch when not in use.

SIDE EFFECTS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and stroke [see BOXED WARNING and WARNINGS AND PRECAUTIONS] Vascular events [see WARNINGS AND PRECAUTIONS] Liver disease [see WARNINGS AND PRECAUTIONS] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache 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. The data presented in Section 6.1 are from a clinical trial conducted with a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets. TAYTULLA is bioequivalent to these norethindrone acetate/ethinyl estradiol tablets. Common Adverse Reactions (≥ 2% of all Treated Subjects) The most common adverse reactions reported by at least 2% of the 743 women using norethindrone acetate/ethinyl estradiol tablets were the following, in order of decreasing incidence: headache (6.3%), vaginal candidiasis (6.1%), nausea (4.6%), menstrual cramps (4.4%), breast tenderness (3.4%), bacterial vaginitis (3.1%), abnormal cervical smear (3.1%), acne (2.7%), mood swings (2.2%), and weight gain (2.0%). Adverse Reactions Leading to Study Discontinuation Among the 743 women using norethindrone acetate/ethinyl estradiol tablets, 46 women (6.2%) withdrew because of an adverse event. Adverse events occurring in 3 or more subjects leading to discontinuation of treatment were, in decreasing order: abnormal or irregular bleeding (1.3%), nausea (0.8%), menstrual cramps (0.5%), and increased blood pressure (0.4%). Postmarketing Experience The following adverse reactions have been identified during post approval use of a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Vascular disorders: thrombosis/embolism (coronary artery, pulmonary, cerebral, deep vein). Hepatobiliary disorders: cholelithiasis, cholecystitis, hepatic adenoma, hemangioma of liver. Immune system disorders: hypersensitivity reaction. Skin and subcutaneous disorders: alopecia, rash (generalized and allergic), pruritus, skin discoloration. GI disorders: nausea, vomiting, abdominal pain. Musculoskeletal and connective tissue disorders: myalgia. Eye disorders: blurred vision, visual impairment, corneal thinning, change in corneal curvature (steepening). Infections and infestations: fungal infection, vaginal infection. Investigations: change in weight or appetite (increase or decrease), fatigue, malaise, peripheral edema, blood pressure increased. Nervous system disorders: headache, dizziness, migraine, loss of consciousness. Psychiatric disorders: mood swings, depression, insomnia, anxiety, suicidal ideation, panic attack, changes in libido. Renal and urinary disorders: cystitis-like syndrome. Reproductive system and breast disorders: breast changes (tenderness, pain, enlargement, and secretion), premenstrual syndrome, dysmenorrhea. Cardiovascular: chest pain, palpitations, tachycardia, myocardial infarction. DRUG INTERACTIONS Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. Effects Of Other Drugs On Combined Oral Contraceptives Substances Diminishing The Efficacy Of COCs Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate and products containing St. John's wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances Increasing The Plasma Concentrations Of COCs Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone concentrations. Human Immunodeficiency Virus (HIV)/ Hepatitis C Virus (HCV) Protease Inhibitors And Nonnucleoside Reverse Transcriptase Inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of coadministration with HIV/HCV 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. Effects Of Combined Oral Contraceptives On Other Drugs COCs containing 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. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs. Interference With Laboratory Tests The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

SIDE EFFECTS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and stroke [see BOXED WARNING and WARNINGS AND PRECAUTIONS] Vascular events [see WARNINGS AND PRECAUTIONS] Liver disease [see WARNINGS AND PRECAUTIONS] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache 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. The safety of LOESTRIN 24 Fe was evaluated in 743 subjects who participated in an open-label, randomized, active-controlled, multicenter clinical trial of LOESTRIN 24 Fe for contraception. This trial examined healthy, non-pregnant volunteers aged 18 to 45 years, who were sexually active and had a body mass index of ≤ 35 kg/m². Subjects were followed for up to six 28-day cycles providing a total of 3,823 treatment-cycles of exposure. Common Adverse Reactions ( ≥ 2% of all subjects): The most common adverse reactions reported by at least 2% of the 743 women using LOESTRIN 24 Fe were the following, in order of decreasing incidence: headache (6.3%), vaginal candidiasis (6.1%), nausea (4.6%), menstrual cramps (4.4%), breast tenderness (3.4%), mood changes (including mood swings (2.2%) and depression (1.1%)), bacterial vaginitis (3.1%), acne (2.7%), and weight gain (2.0%). Adverse Reactions Leading to Study Discontinuation: Among the 743 women using LOESTRIN 24 Fe, 46 women (6.2%) withdrew because of an adverse event. Adverse events occurring in 3 or more subjects leading to discontinuation of treatment were, in decreasing order: abnormal bleeding (0.9%), nausea (0.8%), mood changes (0.8%), menstrual cramps (0.4%), increased blood pressure (0.4%), and irregular bleeding (0.4%). Postmarketing Experience The following adverse reactions have been identified during post approval use of LOESTRIN 24 Fe. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Cardiovascular: chest pain, palpitations, tachycardia, angina pectoris, myocardial infarction. Endocrine disorders: hypothyroidism, hyperthyroidism. Eye disorders: blurred vision, visual impairment, transient blindness, corneal thinning, change in corneal curvature (steepening). GI disorders: nausea, vomiting, abdominal pain, constipation, pancreatitis. Hepatobiliary disorders: cholelithiasis, cholecystitis, hepatic adenoma, hemangioma of liver. Immune system disorders: anaphylactic reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms. Infections: vaginal infection. Metabolism and nutrition disorders: change in weight or appetite (increase or decrease). hypoglycemia, diabetes mellitus, anemia. Musculoskeletal and connective tissue disorders: myalgia. Skin and subcutaneous disorders: alopecia, rash (generalized and allergic), pruritus, skin discoloration, night sweats, swelling face or lips, hirsutism, skin burning sensation, erythema multiforme, erythema nodosum, hemorrhagic eruption. Nervous system disorders: headache, dizziness, migraine, hyperesthesia, paraesthesia, hypoaesthesia, somnolence, loss of consciousness, sensory disturbance. Psychiatric disorders: mood swings, depression, insomnia, anxiety, suicidal ideation, panic attack, changes in libido, bipolar disorder, dissociation, homicidal ideation. Renal and urinary disorders: pollakiuria, dysuria, cystitis-like syndrome. Reproductive system and breast disorders: breast changes (tenderness, pain, enlargement, and secretion), premenstrual syndrome, ovarian cyst, pelvic pain, ovarian cyst ruptured, pelvic fluid collection. Vascular disorders: hot flush, thrombosis/embolism (coronary artery, pulmonary, cerebral, deep vein), migraine, transient ischemic attack, ischemic stroke. DRUG INTERACTIONS Consult the labeling of concurrently used drugs to obtain further information about interactions with oral contraceptives or the potential for enzyme alterations. Effects Of Other Drugs On Combined Oral Contraceptives Substances Decreasing The Plasma Concentrations Of COCs And Potentially Diminishing The Efficacy Of COCs Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of oral contraceptives including phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John's wort. Interactions between COCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances Increasing The Plasma Concentrations Of COCs Co-administration of atorvastatin or rosuvastatin and certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20-25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations. Human Immunodeficiency Virus (HIV)/Hepatitis C virus (HCV) Protease Inhibitors And Non-Nucleoside Reverse Transcriptase Inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritnoavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). Effects Of Combined Oral Contraceptives On Other Drugs COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, and temazepam. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of COCs [see WARNINGS AND PRECAUTIONS]. Interactions With Laboratory Tests The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Thromboembolic Disorders And Other Vascular Problems Stop TAYTULLA if an arterial or deep venous thrombotic event (VTE) occurs. Stop TAYTULLA if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. If feasible, stop TAYTULLA at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE. Start TAYTULLA 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 (> 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. Liver Disease Impaired Liver Function Do not use TAYTULLA in women with acute viral hepatitis or severe (decompensated) cirrhosis of liver [see CONTRAINDICATIONS]. 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 TAYTULLA if jaundice develops. Liver Tumors TAYTULLA is contraindicated in women with benign and malignant liver tumors [see CONTRAINDICATIONS]. 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. High Blood Pressure TAYTULLA is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS]. For women with well-controlled hypertension, monitor blood pressure and stop TAYTULLA 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. 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. Carbohydrate And Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking TAYTULLA. 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 TAYTULLA develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue TAYTULLA if indicated. Consider discontinuation of TAYTULLA in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see CONTRAINDICATIONS]. 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, 24-35% 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 TAYTULLA may experience amenorrhea. In the clinical trial with a 24-day regimen of norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablets, 22 to 36% of the women using norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg 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 capsules 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. 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 TAYTULLA 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]. Depression Carefully observe women with a history of depression and discontinue TAYTULLA if depression recurs to a serious degree. Carcinoma Of The Breast And Cervix TAYTULLA is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally-sensitive [see CONTRAINDICATIONS]. There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. 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. Effect On Binding Globulins The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased. 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. Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma 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 TAYTULLA. Patient Counseling Information See FDA-approved patient labeling (PATIENT INFORMATION). Counsel patients on the following information: Cigarette smoking increases the risk of serious cardiovascular events from COC use, and women who are over 35 years old and smoke should not use COCs. Increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC. TAYTULLA does not protect against HIV infection (AIDS) and other sexually transmitted infections. The Warnings and Precautions associated with COCs. TAYTULLA is not to be used during pregnancy; if pregnancy occurs during use of TAYTULLA, instruct the patient to stop further intake. Take one capsule daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed. See “What to Do if You Miss Capsules” section in FDA-approved patient labeling. Use a back-up or alternative method of contraception when enzyme inducers are used with TAYTULLA. COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established. Women who start COCs postpartum, and who have not yet had a period, should use an additional method of contraception until they have taken a pink capsule for 7 consecutive days. Amenorrhea may occur. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility [See WARNINGS AND PRECAUTIONS and Use In Specific Populations] Use In Specific Populations Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy. The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion. Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk. Pediatric Use Safety and efficacy of TAYTULLA have been established in women of reproductive age. Efficacy is 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. Geriatric Use TAYTULLA has not been studied in postmenopausal women and is not indicated in this population. Renal Impairment The pharmacokinetics of TAYTULLA has not been studied in subjects with renal impairment [see CLINICAL PHARMACOLOGY]. Hepatic Impairment The pharmacokinetics of TAYTULLA has not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. 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 [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Body Mass Index The safety and efficacy of TAYTULLA in women with a body mass index (BMI) > 35 kg/m² has not been evaluated [see Clinical Studies].

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Thrombotic Disorders And Other Vascular Problems Stop LOESTRIN 24 Fe if an arterial thrombotic event or venous thromboembolic (VTE) event occurs. Stop LOESTRIN 24 Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately [see ADVERSE REACTIONS]. If feasible, stop LOESTRIN 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 as well as during the following prolonged immobilization. Start LOESTRIN 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 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COCs and when restarting oral contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs 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). This risk increases with age, particularly in women over 35 years of age who smoke. Use COCs with caution in women with cardiovascular disease risk factors. Liver Disease Impaired Liver Function Do not use LOESTRIN 24 Fe in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see CONTRAINDICATIONS].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 LOESTRIN 24 Fe if jaundice develops. Liver Tumors LOESTRIN 24 Fe is contraindicated in women with benign and malignant liver tumors [see CONTRAINDICATIONS]. 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 risk of liver cancers in COC users is less than one case per million users. High Blood Pressure LOESTRIN 24 Fe is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS]. For women with well-controlled hypertension, monitor blood pressure and stop LOESTRIN 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. Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may 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. Carbohydrate And Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking LOESTRIN 24 Fe. COCs may decrease glucose tolerance. 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 LOESTRIN 24 Fe develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue LOESTRIN 24 Fe if indicated. Consider discontinuation of LOESTRIN 24 Fe in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event). 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 contraceptive product. In a clinical trial of LOESTRIN 24 Fe, the frequency and duration of unscheduled bleeding and/or spotting was assessed in 743 women (3,823 28-day cycles). A total of 10 subjects (1.3%) discontinued LOESTRIN 24 Fe, at least in part, due to bleeding or spotting. Based on data from the clinical trial, [24-38%] of women using LOESTRIN 24 Fe experienced unscheduled bleeding per cycle in the six months of the trial. The percent of women who experienced unscheduled bleeding tended to decrease over time. Amenorrhea And Oligomenorrhea Women who use LOESTRIN 24 Fe may experience absence of withdrawal bleeding, even if they are not pregnant. In the clinical trial with LOESTRIN 24 Fe, 31 to 41% of the women using LOESTRIN 24 Fe did not have a withdrawal menses in at least one of 6 cycles of use. Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs, 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. 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 LOESTRIN 24 Fe use if pregnancy is confirmed. Administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations]. Depression Carefully observe women with a history of depression and discontinue LOESTRIN 24 Fe if depression recurs to a serious degree. Carcinoma Of The Breast And Cervix LOESTRIN 24 Fe is contraindicated in women who currently have or have had breast cancer because breast cancer is a hormonally-sensitive [see CONTRAINDICATIONS]. There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. 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. Effect On Binding Globulins The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased. 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. Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma 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 LOESTRIN 24 Fe. Patient Counseling Information See FDA-approved Patient Labeling (PATIENT INFORMATION and Instructions for Use). Counsel patients about the following information: Cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs [see BOXED WARNING]. Increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC [see WARNINGS AND PRECAUTIONS]. LOESTRIN 24 Fe does not protect against HIV infection (AIDS) and other sexually transmitted diseases. LOESTRIN 24 Fe is not to be used during pregnancy; if pregnancy occurs during use of LOESTRIN 24 Fe instruct the patient to stop further use [see WARNINGS AND PRECAUTIONS]. Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed [see DOSAGE AND ADMINISTRATION]. Use a back-up or alternative method of contraception when enzyme inducers are used with LOESTRIN 24 Fe [see DRUG INTERACTIONS]. COCs may reduce breast milk production; this is less likely to occur if breastfeeding is well established [see Use in Specific Populations]. Women who start COCs postpartum, and who has not yet had a period, must use an additional method of contraception until she has taken a white tablet for 7 consecutive days [see DOSAGE AND ADMINISTRATION]. Amenorrhea may occur. Consider pregnancy in the event of amenorrhea at the time of the first missed period. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles [see WARNINGS AND PRECAUTIONS]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility [See WARNINGS AND PRECAUTIONS and Use in Specific Populations] Use In Specific Populations Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy. Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion. Women who do not breastfeed should not start COCs earlier than 4 weeks postpartum. Nursing Mothers Advise the nursing mother to use another contraceptive method, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk. Pediatric Use Safety and efficacy of LOESTRIN 24 Fe have been established in women of reproductive age. Efficacy is 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. Geriatric Use LOESTRIN 24 Fe has not been studied in postmenopausal women and is not indicated in this population. Hepatic Impairment The pharmacokinetics of LOESTRIN 24 Fe has not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. 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 [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Renal Impairment The pharmacokinetics of LOESTRIN 24 Fe has not been studied in women with renal impairment. Body Mass Index The safety and efficacy of LOESTRIN 24 Fe in women with a body mass index (BMI) > 35 kg/m² has not been evaluated [see Clinical Studies].

WARNINGS Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke. The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes. Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined. Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from References 8 and 9 with the author's permission). For further information, the reader is referred to a text on epidemiological methods. Thromboembolic Disorders and Other Vascular Problems Myocardial infarction An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Figure3) among women who use oral contraceptives. Figure 3 Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see Section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. Thromboembolism An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped. A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least 4 weeks prior to and for 2 weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than 4 to 6 weeks after delivery in women who elect not to breast feed. Cerebrovascular disease Oral contraceptives 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) hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes. In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension . The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension . The attributable risk is also greater in older women. Dose-related risk of vascular disease from oral contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestin and the nature of the progestin used in the contraceptives. The amount and activity of both hormones should be considered in the choice of an oral contraceptive. Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular oral contraceptive, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest dose of estrogen which produces satisfactory results for the patient. Persistence of risk of vascular disease There are two studies which have shown persistence of risk of vascular disease for ever- users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 50 mcg or higher of estrogens. Estimates of Mortality From Contraceptive Use One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 4). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's but not reported until 1983 . However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling. Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (Porter JB, Hunter J, Jick H, et al. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985;66:1-4; and Porter JB, Hershel J, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987;70:29-32), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception. Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective. Table 4: Annual Number of Birth-Related or Method-Related Deaths Associated With Control of Fertility Per 100,000 Nonsterile Women by Fertility Control Method According to Age Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44 No fertility control methods* 7.0 7.4 9.1 14.8 25.7 28.2 Oral contraceptives non-smoker** 0.3 0.5 0.9 1.9 13.8 31.6 Oral contraceptives smoker** 2.2 3.4 6.6 13.5 51.1 117.2 IUD** 0.8 0.8 1.0 1.0 1.4 1.4 Condom* 1.1 1.6 0.7 0.2 0.3 0.4 Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8 Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6 * Deaths are birth related. ** Deaths are method related. Adapted from H.W. Ory, Reference 41. Carcinoma of the Reproductive Organs and Breasts Epidemiologic studies have been conducted examining the relationship between combination oral contraceptives and breast cancer. ESTROSTEP was not included in these studies, and the majority of the combination oral contraceptives used by women in these studies have higher doses of estrogen than ESTROSTEP. These studies suggest that the risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives; however, these studies do not provide evidence for causation. The observed pattern of increased risk of breast cancer diagnosis may be due to earlier detection of breast cancer in combination oral contraceptive users, the biological effects of combination oral contraceptives, or a combination of reasons. The risk appears to decrease over time after combination oral contraceptive discontinuation, and by 10 years after cessation of combination oral contraceptive use, the additional risk disappears. The risk does not appear to increase with duration of use and no consistent relationships have been found with age at first use or doses studied or type of steroid. Most studies show a similar pattern of risk with combination oral contraceptive use regardless of a woman's reproductive history or her family breast cancer history. Breast cancers diagnosed in current or previous combination oral contraceptive users tend to be less clinically advanced than in nonusers. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormonally-sensitive tumor. Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. Hepatic Neoplasia Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after 4 or more years of use. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term ( > 8 years) oral contraceptive users. However, these cancers are extremely rare in the US, and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users. Ocular Lesions There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately. Oral Contraceptive Use Before and During Early Pregnancy Extensive epidemiological 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 insofar as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed. Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens. Carbohydrate and Lipid Metabolic Effects Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance . Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives. A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. Elevated Blood Pressure An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use . Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens. Women with a history of hypertension or hypertension-related diseases or renal disease should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever and never users. Headache The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. Bleeding Irregularities Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Non-hormonal causes should be considered, and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of prolonged breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent. PRECAUTIONS Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. Physical Examination and Follow-Up It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. Lipid Disorders Women who are being treated for hyperlipidemia should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. Liver Function If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function. Fluid Retention Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. Emotional Disorders Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. Contact Lenses Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. Carcinogenesis See WARNINGS section. Pregnancy Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections. Nursing Mothers Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child. Pediatric Use Safety and efficacy of ESTROSTEP have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. Geriatric Use This product has not been studied in women over 65 years of age and is not indicated in this population. Information for the Patient See patient labeling.