LEVONORGESTREL AND ETHINYL ESTRADIOL AND ETHINYL ESTRADIOL

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (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. For this reason, COCs including levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, are contraindicated in women who are over 35 years of age and smoke [see Contraindications (4) and Warnings and Precautions (5.1)].

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are indicated for use by females of reproductive potential to prevent pregnancy.

Begin levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the first white to off-white tablet that day.

For each 91-day course, take in the following order:

1. Take one white to off-white tablet daily for 84 consecutive days. Use a non-hormonal back-up method of contraception (such as condoms or spermicide) until a white to off-white has been taken daily for 7 consecutive days.

2. Then take one light peach tablet for 7 consecutive days. A scheduled period should occur during the 7 days that the light peach tablets are taken.

Begin the next and all subsequent 91-day cycles without interruption on the same day of the week (Sunday) on which the patient began her first dose of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, following the same schedule: 84 days taking a white to off-white tablet followed by 7 days taking a light peach tablet. If the patient does not immediately start her next pill pack, instruct her to protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a white to off-white tablet daily for 7 consecutive days.

Switching to levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets from another oral hormonal contraceptive or from another contraceptive method (transdermal patch, vaginal ring, injection, intrauterine contraceptive, implant)

Start on the Sunday after the patient’s next period starts. Use additional non-hormonal contraceptive (such as condoms and spermicide) until the patient has taken a white to off-white tablet for 7 consecutive days.

Starting Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets after Abortion or Miscarriage

First-trimester

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets may be started on the Sunday after an abortion or miscarriage. The patient must use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a white to off-white tablet for 7 consecutive days.

Second-trimester

Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start contraceptive therapy with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a white to off-white tablet for 7 consecutive days [see Contraindications (4) and Warnings and Precautions (5.1)].

Starting Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets after Childbirth

Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets following the instructions for women not currently using hormonal contraception. Use additional non-hormonal contraception (such as condoms and spermicide) until the patient has taken a white to off-white tablet for 7 consecutive days [see Contraindications (4) and Warnings and Precautions (5.1)].

If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets [see Warnings and Precautions (5.1),Use in Specific Populations (8.1)].

Take one tablet by mouth at the same time every day. The dosage of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets is one white to off-white tablet daily for 84 consecutive days, followed by one light peach tablet daily for 7 days. To achieve maximum contraceptive effectiveness, levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets must be taken exactly as directed, in the order directed, and at intervals not exceeding 24 hours. The failure rate may increase when pills are missed or taken incorrectly.

Table 1. Instructions for Missed Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets

In case of prolonged vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken.

Levonorgestrel and Ethinyl Estradiol Tablets, USP and Ethinyl Estradiol Tablets, USP are available in Extended-Cycle Tablet Blister Pack, each containing a 13-week supply of tablets: 84 white to off-white tablets, each containing 0.1 mg of levonorgestrel and 0.02 mg ethinyl estradiol, and 7 light peach tablets each containing 0.01 mg of ethinyl estradiol. The white to off-white tablets are round, biconvex tablets with 214 debossed on one side and other side plain. The light peach tablets are round, biconvex tablets with 215 debossed on one side and other side plain.

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in females who are known to have or develop the following conditions:

• A high risk of arterial or venous thrombotic diseases. Examples include females who are known to:
• oSmoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)]
• oHave current or history of deep vein thrombosis or pulmonary embolism [see Warnings and Precautions (5.1)]
• oHave cerebrovascular disease [see Warnings and Precautions (5.1)]
• oHave coronary artery disease [see Warnings and Precautions (5.1)]
• oHave thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)]
• oHave inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)]
• oHave uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions (5.5)]
• oHave diabetes mellitus and are over age 35, diabetes mellitus with hypertension or with vascular disease or other end-organ damage, or diabetes mellitus of > 20 years duration [see Warnings and Precautions (5.7)]
• oHave headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see Warnings and Precautions (5.8)]
• Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions (5.2)]
• Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions (5.2)]
• Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8)]
• Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions (5.4)].

• Stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if an arterial or deep venous thrombotic/thromboembolic event occurs.
• Stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately.
• Discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets during prolonged immobilization. If feasible, stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery, or other surgeries known to have an elevated risk of thromboembolism.
• Start levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets no earlier than 4 weeks after delivery, in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
• Before starting levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in females with a high risk of arterial or venous/thromboembolic diseases [see Contraindications (4)].

Arterial Events

COCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (>35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity.

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in women over 35 years of age who smoke [see Contraindications (4)]. Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

Venous Events

Use of COCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs [see Contraindications (4)]. While the increased risk of VTE associated with use of COCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman years.

The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

Use of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets provides females with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing the same strength synthetic estrogens and progestins (an additional 9 and 13 weeks of exposure to progestin and estrogen, respectively, per year).

Elevated Liver Enzymes

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4)]. Acute liver test abnormalities may necessitate the discontinuation of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets until the liver tests return to normal and levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets causation has been excluded. Discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if jaundice develops.

Liver Tumors

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in females with benign or malignant liver tumors [see Contraindications (4)]. COCs increase the risk of hepatic adenomas. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death from abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. The attributable risk of liver cancers in COC users is less than one case per million users.

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For all females, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if blood pressure rises significantly.

An increase in blood pressure has been reported in females taking COCs, and this increase is more likely in older women and with extended duration of use. The effect of COCs on blood pressure may vary according to the progestin in the COC.

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increases with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate COC use in younger females, are contraindications to use in women over 35 years of age [see Contraindications (4) and Warnings and Precautions (5.1)]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating a COC for women over 35 years, such as:

• Hypertension
• Diabetes
• Dyslipidemia
• Obesity

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs, including levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, may also worsen existing gallbladder disease.

A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.

1. Hyperglycemia

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in diabetic women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease, or females with diabetes of > 20 years duration [see Contraindications (4)]. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are taking COCs.

Dyslipidemia

Consider alternative contraception for females with uncontrolled dyslipidemias. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets may cause adverse lipid changes.

Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, which may increase the risk of pancreatitis.

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in women over 35 years of age who have migraine headaches with or without aura [see Contraindications (4)].

If a woman taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if indicated. Consider discontinuation of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if there is an increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

Unscheduled Bleeding and Spotting

Females using levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first 3 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.

When prescribing levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, the occurrence of fewer planned menses (4 per year instead of 13 per year) should be weighed against the occurrence of increased unscheduled bleeding and/or spotting. The clinical trial that evaluated the efficacy of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets also assessed unscheduled bleeding. The participants in this 12-month clinical trial (N=2,185) completed the equivalent of over 20,000 28-day cycles of exposure and were composed primarily of women who had used OCs previously (89%), as opposed to new users (11%). A total of 209 subjects (9.6%) discontinued levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, at least in part, due to bleeding and/or spotting.

Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with an average of 2-3 days of bleeding and/or spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 2 below presents the number of days with unscheduled bleeding in treatment cycles 1 and 4. Table 3 presents the number of days with unscheduled spotting in treatment cycles 1 and 4.

Figure 2 shows the percentage of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets subjects participating in the primary clinical trial with ≥ 7 days or ≥ 20 days of unscheduled bleeding and/or spotting, or just unscheduled bleeding, during each 91-day treatment cycle.

Figure 2. Percent of Women Taking Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets who Reported Unscheduled Bleeding and/or Spotting (Based on Daily Diaries)

If unscheduled spotting or bleeding occurs, instruct the patient to continue on the same regimen. If the bleeding is persistent or prolonged, advise the patient to consult her healthcare provider.

Amenorrhea and Oligomenorrhea

Females who use levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant.

If scheduled bleeding does not occur, consider the possibility of pregnancy.

After discontinuation of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

Carefully observe females with a history of depression and discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if depression recurs to a serious degree. Data on the association of COCs with the onset of depression or exacerbation of existing depression are limited.

Breast Cancer

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].

Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience (6.2)].

Cervical Cancer

Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings are due to differences in sexual behavior and other factors.

The estrogen component of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets 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.

In females with hereditary angioedema, exogenous estrogens, including levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, may induce or exacerbate symptoms of hereditary angioedema.

Chloasma may occur with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets use, especially in females with a history of chloasma gravidarum. Advise females with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while using levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:

• Serious cardiovascular events and smoking [see Boxed Warning and Warnings and Precautions (5.1)]
• Vascular events [see Warnings and Precautions (5.1)]
• Liver disease [see Warnings and Precautions (5.2)]

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 clinical trial that evaluated the safety and efficacy of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets was a 12-month, multicenter, non-comparative open-label study, which enrolled women aged 18-41, of whom 2,185 took at least one dose of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

Adverse Reactions Leading to Study Discontinuation: 11% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions leading to discontinuation were irregular and/or heavy uterine bleeding, headache, mood changes, nausea, acne, and weight gain.

Common Treatment-Emergent Adverse Reactions (≥ 5% of women): headaches (33%); irregular and/or heavy uterine bleeding (13%), dysmenorrhea (11%), nausea and/or vomiting (11%), back pain (8%).

Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 3).

Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use.

Figure 3: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives

RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs.

The sections below provide information on substances for which data on drug interactions with COCs are available. There is little information available about the clinical effect of most drug interactions that may affect COCs. However, based on the known pharmacokinetic effects of these drugs, clinical strategies to minimize any potential adverse effect on contraceptive effectiveness or safety are suggested.

Consult the approved product labeling of all concurrently used drugs to obtain further information about interactions with COCs or the potential for metabolic enzyme or transporter system alterations.

No formal drug-drug interaction studies were conducted with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

Substances Decreasing the Plasma Concentrations of COCs and Potentially Diminishing the Efficacy of COCs:

Table 4 includes substances that demonstrated an important drug interaction with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

Table 4: Significant Drug Interactions Involving Substances That Affect COCs

^a Induction potency of St. John’s wort may vary widely based on preparation.

Substances increasing the systemic exposure of COCs:

Co-administration of atorvastatin or rosuvastatin and COCs containing ethinyl estradiol increase systemic exposure of ethinyl estradiol by approximately 20 to 25 percent. Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation. CYP3A inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of COCs.

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) protease inhibitors and nonnucleoside reverse transcriptase inhibitors:

Significant decreases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with some HIV protease inhibitors (e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir), some HCV protease inhibitors (e.g., boceprevir and telaprevir), and some non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine).

In contrast, significant increases in systemic exposure of the estrogen and/or progestin have been noted when COCs are co-administered with certain other HIV protease inhibitors (e.g., indinavir and atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (e.g., etravirine).

Table 5 provides significant drug interaction information for drugs co-administered with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

Co-administration of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir is contraindicated due to potential for ALT elevations [see Warnings and Precautions (5.4)]. Co-administration of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets and glecaprevir/pibrentasvir is not recommended due to potential for ALT elevations.

The use of COCs may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

Risk Summary

There is no use for contraception in pregnancy; therefore, levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets should be discontinued during 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 COCs before conception or during early pregnancy.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively.

1. Risk Summary

Contraceptive hormones and/or metabolites are present in human milk. COCs can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breastfeeding [See Dosage and Administration (2.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets and any potential adverse effects on the breastfed child from levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets or the underlying maternal condition.

Safety and efficacy of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of this product before menarche is not indicated.

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets have not been studied in postmenopausal women and is not indicated in this population.

The pharmacokinetics of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets have not been studied in subjects with hepatic impairment. However, COCs may be poorly metabolized in patients with hepatic impairment. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are contraindicated in females with acute hepatitis or severe decompensated cirrhosis [see Contraindications (4) and Warnings and Precautions (5.2)].

COCs prevent pregnancy primarily by suppressing ovulation.

No pharmacodynamic studies were conducted with levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

Absorption

No specific investigation of the absolute bioavailability of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the systemic bioavailability of ethinyl estradiol is approximately 43%.

The mean plasma pharmacokinetic parameters of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets following a single oral dose of three levonorgestrel and ethinyl estradiol combination tablets in normal healthy women under fasting conditions are reported in Table 6.

The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets has not been evaluated.

Distribution

The apparent volume of distribution of levonorgestrel and ethinyl estradiol is reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Ethinyl estradiol is about 95 to 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of combination levonorgestrel and ethinyl estradiol OCs, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose pharmacokinetics, due in part, to increased SHBG levels that are induced by ethinyl estradiol, and a possible reduction in hepatic metabolic capacity.

Metabolism

Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.

First-pass metabolism of ethinyl estradiol involves formation of ethinyl estradiol-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed ethinyl estradiol by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol hydroxylation. Hydroxylation at the 4-, 6-, and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.

Excretion

About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and then undergoes enterohepatic recirculation.

Race

The effect of race on the pharmacokinetics of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets has not been evaluated.

[See Warnings and Precautions (5.2,5.11)]

WARNING TO WOMEN WHO SMOKE

Do not use levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects 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.

What is the most important information I should know about levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets?

Do not use levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects 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.

What Are Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets?

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are a birth birth control pill (hormonal contraceptive) used by women to prevent pregnancy. It contains two female hormones, an estrogen called ethinyl estradiol, and a progestin called levonorgestrel. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets do not protect against HIV infection (AIDS) and other sexually transmitted infections.

How do Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets Work for contraception?

Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The more carefully you follow the directions, the less chance you have of getting pregnant.

Based on the results of a single clinical study lasting 12 months, 2 to 4 women, out of 100 women, may get pregnant during the first year they use levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

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 levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets?

Do not take levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if you:

• smoke and are over 35 years of age
• have or had blood clots in your arms, legs, eyes or lungs
• had a stroke
• had a heart attack
• have certain heart valve problems or heart rhythm abnormalities that can cause blood clots to form in the heart
• have an inherited problem with your blood that makes it clot more than normal
• have high blood pressure that cannot be controlled by medicine or have high blood pressure with blood vessel problems
• have diabetes and are over the age of 35; have diabetes with high blood pressure; kidney, eye, nerve, or blood vessel damage; or for more than 20 years
• have certain kinds of severe migraine headaches with aura, numbness, weakness or changes in vision, or any migraine headaches if you are over the age of 35
• have or had breast cancer
• have liver disease, including liver tumors
• have unexplained vaginal bleeding
• take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme “alanine aminotransferase” (ALT) in the blood.
• If any of these conditions happen to you while you are taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, stop taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets right away and talk to your healthcare provider. Use non-hormonal contraception (such as condoms and spermicide) when you stop taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

What should I tell my healthcare provider before taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets?

• are pregnant or think you may be pregnant
• are scheduled for surgery. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets may increase your risk of blood clots after surgery. You should stop taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets at least 4 weeks before you have surgery and not restart levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets until at least 2 weeks after your surgery.
• 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. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets may decrease the amount of breast milk you make. A small amount of the hormones in levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets 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 if you have ever had any of the conditions listed in, “Who should not take levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets” above. Your healthcare provider may recommend another method of birth control.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets may affect the way other medicines work, and other medicines may affect how well levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets work.

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 physician may need to adjust the dose of lamotrigine.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone.

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 levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets?

Read the Instructions for Use at the end of this Patient Information.

What are the most serious risks of taking birth control pills?

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 over 35 years old. 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 (thrombophlebitis)
• Lungs (pulmonary embolus)
• Eyes (loss of eyesight)
• Heart (heart attack)
• Brain (stroke)

A few women who take birth control pills may get:

• High blood pressure. You should see your healthcare provider to check your blood pressure regularly.
• 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 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 eyes

What are 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 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 changes

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 1-800FDA-1088.

No serious problems have been reported from a birth control pill overdose, even when accidentally taken by children.

What else should I know about taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets?

• If you are scheduled for any lab tests, tell your healthcare provider you are taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. Certain blood tests may be affected by levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.
• Do not skip any pills, even if you do not have sex often.
• 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 levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets at least four weeks before you have major surgery and not restart it for 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 levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, may decrease the amount of milk you make. A small amount of the pill's hormones pass into breast milk, but this has not caused harmful effects in breastfeeding infants.
• If you have vomiting or diarrhea, your birth control pills may not work as well. Use another birth control method, like condoms or a spermicide, until you check with your healthcare provider.

How should I store levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets?

• Store levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets and all medicines out of the reach of children.

General information about the safe and effective use of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets for a condition for which it was not prescribed. Do not give levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets to anyone else.

This Patient Information summarizes the most important information about levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. If you have concerns or questions, ask your healthcare provider. You may also ask your healthcare providers for a more detailed label written for medical professionals.

Do birth control pills cause cancer?

It is not known if hormonal birth control pills cause breast cancer. Some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use.

If you have breast cancer now, or have had it in the past, do not use hormonal birth control 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 levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets?

When you take levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, which has a 91-day extended dosing cycle, you should expect to have 4 scheduled periods per year (bleeding when you are taking the 7 light peach pills). Each period is likely to last about 2 to 3 days. However, you will probably have more bleeding or spotting between your scheduled periods than if you were using a birth control pill with a 28-day dosing cycle. This bleeding or spotting tends to decrease with time. Do not stop taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets because of this bleeding or spotting. If the spotting continues for more than 7 consecutive days or if the bleeding is heavy, call your healthcare provider.

What if I miss my scheduled period when taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets?

You should consider the possibility that you are pregnant if you miss your scheduled period (no bleeding on the days that you are taking light peach tablets). Since scheduled periods are less frequent when you are taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, notify your healthcare provider that you have missed your period and that you are taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. Also notify your healthcare provider if you have symptoms of pregnancy such as morning sickness or unusual breast tenderness. It is important that your healthcare provider evaluates you to determine if you are pregnant. Stop taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if it is determined that you are pregnant.

What are the ingredients in levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets?

Active ingredients:

white to off-white tablets: levonorgestrel and ethinyl estradiol

light peach tablets: ethinyl estradiol

Inactive ingredients:

White to off-white tablets: lactose monohydrate, magnesium stearate and polacrilin potassium.

Light peach tablets: anhydrous lactose, dl-α-tocopherol, FD&C Yellow No. 6 (Sunset Yellow) Aluminum Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone k-25 and polacrilin potassium.

INSTRUCTIONS FOR USE

Levonorgestrel and Ethinyl Estradiol Tablets USP, (0.1 mg/0.02 mg) and Ethinyl Estradiol Tablets USP, (0.01 mg)

How do I take levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets?

1. 1.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.
2. 2.Many women have spotting or light bleeding, or may feel sick to their stomach during the first few months of taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. If you 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 healthcare provider.
3. 3.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, you could also feel a little sick to your stomach.
4. 4.If you have trouble remembering to take levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, talk to your healthcare provider about how to make pill-taking easier or about using another method of birth control.

Before you start taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets

1. 1.Decide what time of day you want to take your pill. It is important to take it at about the same time every day.
2. 2.Look at your Extended-Cycle Tablet Blister Pack. Your Tablet Blister Pack consists of 3 blisters with cards that hold 91 individually sealed pills (a 13-week or 91-day cycle). The 91 pills consist of 84 white to off-white and 7 light peach pills. Blisters 1 and 2 each contain 28 white to off-white pills (4 rows of 7 pills). Blister 3 contains 35 pills consisting of 28 white to off-white pills (4 rows of 7 pills) and 7 light peach pills (1 row of 7 pills).

1. 3.Also find:
   1. Where on the first blister pack to start taking pills (upper left corner at the start arrow) and
   2. In what order to take the pills (follow the weeks and arrow).
2. 4.Be sure you have ready at all times another kind of birth control (such as condoms or spermicides), to use as a back-up in case you miss pills.

When to start levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets

1. 1.Take the first white to off-white pill on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the first white to off-white pill that same day.
2. 2.Use another method of birth control (such as condoms or spermicides) as a back-up method if you have sex anytime from the Sunday you start your first white to off-white pill until the next Sunday (first 7 days). If you have been using a different hormonal method of birth control (such as a different pill, the “patch,” or the “vaginal ring”), you need to use another method of birth control (such as condoms or spermicides) each time you have sex after stopping your old method of birth control until you have taken levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets for 7 days.

If you are switching from another birth control method:

If you have been using a different hormonal method of birth control (such as a different pill, the “patch,” or the “vaginal ring”), you need to use another method of birth control (such as condoms or spermicides) each time you have sex after stopping your old method of birth control until you have taken levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets for 7 days.

If you have recently given birth and have not yet had a period, use another method of birth control if you have sex (such as condoms and spermicides) as a back-up method until you have taken levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets for 7 days.

How to take levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets

1. 1.Take one pill at the same time every day until you have taken the last pill in the tablet blister pack.
   1. Do not skip pills even if you are experiencing spotting or bleeding or feel sick to your stomach (nausea).
   2. Do not skip pills even if you do not have sex very often.
2. 2.When you finish a tablet blister pack
   1. After taking the last light peach pill, start taking the first white to off-white pill from a new Extended-Cycle Tablet Blister Pack the very next day (this should be on a Sunday) regardless of when your period started.
3. 3.If you miss your scheduled period when you are taking the light peach pills, contact your healthcare provider because you may be pregnant. If you are pregnant, you should stop taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

What To Do If You Miss Pills

If you MISS 1 white to off-white pill:

1. 1.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.
2. 2.You do not need to use a back-up birth control method if you have sex.

If you MISS 2 white to off-white pills in a row:

1. 1.Take 2 pills on the day you remember, and 2 pills the next day.
2. 2.Then take 1 pill a day until you finish the pack.
3. 3.You could become pregnant if you have sex in the 7 days after you miss two pills. You MUST use another birth control method (such as condoms or spermicide) as a back up for the 7 days after you restart your pills.

If you MISS 3 OR MORE white to off-white pills in a row:

1. 1.Do not take the missed pills. Keep taking 1 pill every day as indicated on the pack until you have completed all of the remaining pills in the pack. For example: If you resume taking the pill on Thursday, take the pill under “Thursday” and do not take the missed pills. You may experience bleeding during the week following the missed pills.
2. 2.You could become pregnant if you have sex during the days of missed pills or during the first 7 days after restarting your pills.
3. 3.You MUST use a non-hormonal birth control method (such as condoms or spermicide) as a back-up when you miss pills and for the first 7 days after you restart your pills. If you do not have your period when you are taking the light peach pills, call your healthcare provider because you may be pregnant.

If you MISS ANY of the 7 light peach pills:

1. 1.Throw away the missed pills.
2. 2.Keep taking the scheduled pills until the pack is finished.
3. 3.You do not need a back-up method of birth control.

Finally, if you are still not sure what to do about the pills you have missed

1. 1.Use a back-up method anytime you have sex.
2. 2.Keep taking one pill each day until you contact your healthcare provider.

If you have any questions or are unsure about the information in this leaflet, call your healthcare provider.

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Manufactured by:
Mylan Laboratories Limited
Ahmedabad- 382 213, India
Code No.: GUJ-DRUGS/G/28/1297

75096643

Revised: 4/2023
FC:OT:7284:R10