Lupin

Levonorgestrel + ethinyl estradiol

Generic

Generic for Daysee

ID: 68180084613

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LEVONORGESTREL ETHINYL ESTRADIOL 015 MG 30 MCG 10 MCG TABLET 6818084613

📜 Prescription Required

FORM

Tablet

STRENGTH

0.15 mg/30 mcg-10 mcg

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TL;DR — Quick Summary

Key facts from the full medication guide below

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS RECENT MAJOR CHANGES 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 How to Start and Take Daysee

🩺What it's for

Daysee is indicated for use by females of reproductive potential to prevent pregnancy. Daysee is a combination of levonorgestrel, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive to potential prevent pregnancy.

💊How to take it

Take one tablet daily by mouth at the same time every day for 91 days in the order directed on the blister pack.

ℹ️Common side effects

Hyperglycemia Daysee is 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)]. Daysee may decrease glucose tolerance. Carefully monitor prediabetic and diabetic women who are taking Daysee. Dyslipidemia Consider alternative contraception for women with uncontrolled dyslipidemia. Daysee may cause adverse lipid changes.

⚠️Serious risks

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, including Daysee, are contraindicated in women who are over 35 years of age and smoke. [See Contraindications (4) and Warnings and Precautions (5.1).].

📋Interactions & cautions

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.

📦Storage & missed dose

How Supplied Daysee [levonorgestrel and ethinyl estradiol tablets USP (0.15 mg/0.03 mg) and ethinyl estradiol tablets USP (0.01 mg)] are available in Extended-Cycle Wallets each containing a 13-week supply of tablets: 84 light blue tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg of ethinyl estradiol, and 7 mustard tablets, each containing 0.01 mg of ethinyl estradiol. Table 1. Instructions for Missed Daysee Tablets If one light blue tablet is missed Take the missed tablet as soon as possible. Take the next tablet at the regular time. Continue taking one tablet a day until the pack is finished. A back-up birth control method is not required if the patient has sex. If two light blue tablet in a row are missed Take the two missed tablets as soon as possible, and the next two tablets the next day. Continue taking one tablet a day until the pack is finished.

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Levonorgestrel + Ethinyl Estradiol (Daysee • [Generic for Seasonique]) Prices

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Begin Daysee on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the first light blue tablet that day. For each 91-day course, take in the following order: Start the first blue tablet on the first Sunday after onset of menstruation. Then take one light blue tablet daily for 84 consecutive days. Use a non-hormonal back-up method of contraception (such as condoms and spermicide) until a light blue tablet has been taken daily for 7 consecutive days. Then take one mustard tablet for 7 consecutive days. Bleeding should occur during the 7 days that the mustard 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 Daysee, following the same schedule: 84 days taking a light blue tablet followed by 7 days taking a mustard 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 light blue tablet daily for 7 consecutive days. Switching to Daysee 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 light blue tablet for 7 consecutive days. Starting Daysee after Abortion or Miscarriage First-trimester Daysee 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 light blue 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 Daysee 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 light blue tablet for 7 consecutive days [see Contraindications (4) and Warnings and Precautions (5.1)]. Starting Daysee after Childbirth Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Daysee 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 light blue 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 Daysee [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)].

Daysee is contraindicated in females who are known to have or develop the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include females who are known to: Smoke, if over age 35 [see Boxed Warnings and Warnings and Precautions (5.1)]. Have current or history of deep vein thrombosis or pulmonary embolism [see Warnings and Precautions (5.1)]. Have cerebrovascular disease [see Warnings and Precautions (5.1)] Have coronary artery disease [see Warnings and Precautions (5.1)]. Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)]. Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)]. Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions (5.3)]. Have 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)]. Have 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 (5.11)]. Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see WARNINGS AND Warnings and Precautions (5.2) and Use in Specific Populations (8.6)]. Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.9)] Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions (5.4)]. A high risk of arterial or venous thrombotic diseases (4) Undiagnosed abnormal uterine bleeding (4) Breast cancer (4) Liver tumors or liver disease, acute viral hepatitis or decompensated cirrhosis (4) Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. (4)

Stop Daysee if an arterial or deep venous thrombotic/thrombembolic event occurs. Stop Daysee if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. Discontinue Daysee during prolonged immobilization. If feasible, stop Daysee at least 4 weeks before and through 2 weeks after major surgery, or other surgeries known to have an elevated risk of thromboembolism. Start Daysee no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. Before starting Daysee evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Daysee is contraindicated in women 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. Daysee is 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 CHCs [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 women who are not pregnant and do not use oral contraceptives, for women who use oral contraceptives, and for women in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these women will develop a VTE. Use of Daysee provides women 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).

Unscheduled Bleeding and Spotting Women using Daysee 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 unscheduled bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy. When prescribing Daysee, 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 primary clinical trial (PSE-301) that evaluated the efficacy of Daysee also assessed unscheduled bleeding. The participants in the 12-month clinical trial (N=1,006) completed the equivalent of 8,681 28-day cycles of exposure and were composed primarily of women who had used oral contraceptives previously (89%) as opposed to new users (11%). A total of 82 (8.2%) of the women discontinued Daysee, at least in part, due to bleeding or spotting. Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with an average of 3 days of bleeding and/or spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 1 below presents the number of days with unscheduled bleeding in treatment cycles 1 and 4. Table 2 presents the number of days with unscheduled spotting in treatment cycles 1 and 4. Table 2: Total Number of Days with Unscheduled Bleeding Q1 = Quartile 1: 25% of women had this number of days of unscheduled bleeding Median: 50% of women had this number of days of unscheduled bleeding Q3 = Quartile 3: 75% of women had this number of days of unscheduled bleeding 91-Day Treatment Cycle Days per 84-Day Interval Days per 28-Day Interval Q1 Median Q3 Mean Mean 1st 1 4 10 6.9 1.7 4th 0 1 4 3.2 0.8 Table 3: Total Number of Days with Unscheduled Spotting Q1 = Quartile 1: 25% of women had this number of days of unscheduled spotting Median: 50% of women had this number of days of unscheduled spotting Q3 = Quartile 3: 75% of women had 5 this number of days of unscheduled spotting 91-Day Treatment Cycle Days per 84-Day Interval Days per 28-Day Interval Q1 Median Q3 Mean Mean 1st 1 4 11 7.4 1.9 4th 0 2 7 4.4 1.1 Figure 2 shows the percentage of Daysee subjects participating in trial PSE-301 with 7 days or 20 days of unscheduled bleeding and/or spotting, or only unscheduled bleeding, during each 91-day treatment cycle. Figure 2: Percent of Women Taking Daysee who Reported Unscheduled Bleeding and/or Spotting or only Unscheduled Bleeding 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 Women who use Daysee 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 Daysee, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

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 to 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 3). 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 following adverse reactions have been identified during post-approval use of Daysee. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency of establish a causal relationship to drug exposure. Gastrointestinal disorders: abdominal distension, vomiting General disorders and administration site conditions: Chest pain, fatigue, malaise, edema peripheral, pain Immune system disorders: hypersensitivity reaction Investigations: blood pressure increased Musculoskeletal and connective tissue disorders: muscle spasms, pain in extremity Nervous system disorders: dizziness, loss of consciousness Psychiatric disorders: insomnia Reproductive and breast disorders: dysmenorrhea Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary thrombosis Skin and subcutaneous tissue disorders: alopecia Vascular disorders: thrombosis

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 Daysee. Table 4: Significant Drug Interactions Involving Substances That Affect COCs Metabolic Enzyme Inducers Clinical effect Concomitant use of COCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of COCs. Decreased exposure of the estrogen and/or progestin component of COCs may potentially diminish the effectiveness of COCs and may lead to contraceptive failure or an increase in breakthrough bleeding. Prevention or management Counsel females to use an alternative method of contraception or a backup method when enzyme inducers are used with COCs. Continue backup contraception for 28 days after discontinuing the enzyme inducer to maintain contraceptive reliability. Examples Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, rufinamide, topiramate, products containing St. John's wortInduction potency of St. John's wort may vary widely based on preparation., and certain protease inhibitors (see separate section on protease inhibitors below). Colesevelam Clinical effect Concomitant use of COCs with colesevelam significantly decreases systemic exposure of ethinyl estradiol. Decreased exposure of the estrogen component of COCs may potentially reduce contraceptive efficacy or result in an increase in breakthrough bleeding, depending on the strength of ethinyl estradiol in the CHC. Prevention or management Administer 4 or more hours apart to attenuate this drug interaction. 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 non-nucleoside 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).

Absorption Ethinyl estradiol and levonorgestrel are absorbed with maximum plasma concentrations occurring within 2 hours after Daysee administration. Levonorgestrel is completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is approximately 43%. The daily exposure to levonorgestrel and ethinyl estradiol on Day 21, corresponding to the end of a typical 3-week contraceptive regimen, and on Day 84, at the end of an extended cycle regimen, were similar. There was no additional accumulation of ethinyl estradiol after dosing a 0.03 mg ethinyl estradiol tablet during Days 84-91. The mean plasma pharmacokinetic parameters of Daysee following a single dose of one levonorgestrel/ethinyl estradiol combination tablet, for 84 days, in normal healthy women are reported in Table 6. Table 6: Mean Pharmacokinetic Parameters for Daysee during Daily One Tablet Dosing for 84 Days AUC 0-24 hr (mean SD) Cmax (mean SD) Tmax (mean SD) Levonorgestrel Day 1 18.2 6.1 ng.hr/mL 3.0 1.0 ng/mL 1.3 0.4 hours Day 21 64.4 25.1 ng.hr/mL 6.2 1.6 ng/mL 1.3 0.4 hours Day 84 60.2 24.6 ng.hr/mL 5.5 1.6 ng/mL 1.3 0.3 hours Ethinyl Estradiol Day 1 509.3 172.0 pg.hr/mL 69.8 26 pg/mL 1.5 0.3 hours Day 21 837.1 271.2 pg.hr/mL 99.6 31 pg/mL 1.5 0.3 hours Day 84 791.5 215.0 pg.hr/mL 91.3 32 pg/mL 1.6 0.3 hours The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Daysee has not been evaluated. Distribution The apparent volume of distribution of levonorgestrel and ethinyl estradiol are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5 - 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Ethinyl estradiol is about 95 - 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 levonorgestrel/ethinyl estradiol oral contraceptives, 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 17 -OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3 , 5 -tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3 , 5 -tetrahydrolevonorgestrel and 16 -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. The terminal elimination half-life for levonorgestrel after a single dose of Daysee was about 34 hours. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of ethinyl estradiol after a single dose of Daysee was found to be about 18 hours. Race The effect of race on the pharmacokinetics of Daysee has not been evaluated.

Advise the patient to read the FDA-approved Patient Labeling (Patient Information and Instructions for Use). Counsel patients about the following information: Cigarette Smoking Cigarette smoking increases the risk of serious cardiovascular events from COC use. Women who are over 35 years old and smoke should not use Daysee [see Boxed Warning and Warnings and Precautions. (5.1)]. Venous Thromboembolism 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 interruption in intake) the same or a different COC [see Warnings and Precautions (5.1)]. Use during Pregnancy Instruct females to stop further intake of Daysee if pregnancy is confirmed during treatment. Sexually Transmitted Infections Daysee does not protect against HIV-infection (AIDS) and other sexually transmitted infections. Dosing and Missed Pill Instructions Patients should take one tablet 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 Pills" section of FDA-Approved Instructions for Use [see Dosage and Administration (2.3)]. Need for Additional Contraception Postpartum females who have not yet had a period when they start Daysee need to use an additional method of contraception until they have taken a light blue tablet for 7 consecutive days [see Dosage and Administration (2.1)]. There is a need to use a back-up or alternative method of contraception when enzyme inducers are used with Daysee [see Drug Interactions (7.1)]. Lactation Daysee may reduce breast milk production. This is less likely to occur if breastfeeding is well established. When possible, nursing women should use other methods of contraception until they have discontinued breastfeeding [see Use in Specific Populations (8.2)]. Amenorrhea and Possible Symptoms of Pregnancy Amenorrhea may occur. Advise patients to contact a healthcare provider in the event of amenorrhea with symptoms of pregnancy, such as morning sickness or unusual breast tenderness [see Warnings and Precautions (5.9)]. Fertility Following Discontinuation of Daysee Resumption of pre-treatment ovarian function is expected, generally within 8 weeks after discontinuation of Daysee. Depression Depressed mood and depression may occur. Women should contact their healthcare provider if mood changes and depressive symptoms occur, including shortly after initiating the treatment [see Warnings and Precautions (5.10)].