forty six Simpesse Generic Name: levonorgestrel and ethinyl estradiol and ethinyl estradiol Dosage Form: kit Side Effects Dosage Professional Interactions Pregnancy More User Reviews Support Group Q & A WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS 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. [See Contraindications (4) .] 1. INDICATIONS AND USAGE Simpesse TM (levonorgestrel and ethinyl estradiol tablets USP and ethinyl estradiol tablets USP) is indicated for use by women to prevent pregnancy. Slideshow Emergency Contraception Laid Bare - The 10 Biggest Myths Revealed 2. DOSAGE AND ADMINISTRATION Take one tablet by mouth at the same time every day. The dosage of Simpesse is one white tablet containing levonorgestrel and ethinyl estradiol daily for 84 consecutive days, followed by one light blue ethinyl estradiol tablet for 7 days. To achieve maximum contraceptive effectiveness, Simpesse must be taken exactly as directed and at intervals not exceeding 24 hours. Instruct the patient to begin taking Simpesse on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first white tablet is taken that day. One white tablet should be taken daily for 84 consecutive days, followed by one light blue tablet for 7 consecutive days. A non-hormonal back-up method of contraception (such as condoms or spermicide) should be used until a white tablet has been taken daily for 7 consecutive days. A scheduled period should occur during the 7 days that the light blue 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 Simpesse, following the same schedule: 84 days taking a white tablet followed by 7 days taking a light blue tablet. If the patient does not immediately start her next pill pack, she should protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a white tablet daily for 7 consecutive days. 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. For patient instructions regarding missed pills, see FDA-Approved Patient Labeling . For postpartum women who are not breastfeeding, start Simpesse no earlier than four to six weeks postpartum due to increased risk of thromboembolism. If the patient starts on Simpesse 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 a white tablet for 7 consecutive days. 3. DOSAGE FORMS AND STRENGTHS Simpesse tablets (levonorgestrel and ethinyl estradiol tablets, USP and ethinyl estradiol tablets, USP) are available in Extended-Cycle Wallets, each containing a 13-week supply of tablets: 84 white tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 light blue tablets each containing 0.01 mg of ethinyl estradiol. The white tablets are round, biconvex, beveled-edge, debossed with S on one side and 27 on other side. The light blue tablets are mottled, round, biconvex, beveled-edge, debossed with S on one side and 45 on other side. 4. CONTRAINDICATIONS Do not prescribe Simpesse to women who are known to have the following: A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: - Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1) ]. - Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1) ]. - Have cerebrovascular disease [see Warnings and Precautions (5.1) ] - Have coronary artery disease [see Warnings and Precautions (5.1) ]. - Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1) ]. - Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1) ]. - Have uncontrolled hypertension [see Warnings and Precautions (5.5) ]. - Have diabetes with vascular disease [see Warnings and Precautions (5.7) ]. - Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions (5.8) ]. Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.9) ]. Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.2) ]. Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6) ]. Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1) ]. 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) ]. 5. WARNINGS AND PRECAUTIONS Thrombotic and Other Vascular Events Stop Simpesse if an arterial or deep venous thrombotic event occurs. Although the use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The excess risk is highest during the first year of use of a COC. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued. Use of Simpesse 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). If feasible, stop Simpesse at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start Simpesse no earlier than 4 to 6 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), and hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. Stop Simpesse if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. Carcinoma of the Breast and Cervix Women who currently have or have had breast cancer should not use Simpesse because breast cancer may be hormonally sensitive. 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 are due to differences in sexual behavior and other factors. Liver Disease Discontinue Simpesse if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users. Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use. Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains obmitasvir/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 Simpesse prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4) ]. Simpesse can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop Simpesse if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking Simpesse. 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 Simpesse develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Simpesse if indicated. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC. Bleeding Irregularities Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If bleeding persists, 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. When prescribing Simpesse, the convenience of fewer planned menses (4 per year instead of 13 per year) should be weighed against the inconvenience of increased unscheduled bleeding and/or spotting. The primary clinical trial (PSE-301) that evaluated the efficacy of Simpesse 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 Simpesse, 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 1: 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 2: 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 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 1 shows the percentage of Simpesse 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. Amenorrhea sometimes occurs in women who are using COCs. Pregnancy should be ruled out in the event of amenorrhea. Some women may encounter amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent. COC Use Before or 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 in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. Oral contraceptive use should be discontinued if pregnancy is confirmed. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1) ] . Emotional Disorders Women with a history of depression should be carefully observed and Simpesse discontinued if depression recurs to a serious degree. Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid binding globulin increase with use of COCs. 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 health care. Other Conditions In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. 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 COCs. 6. ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and smoking [see Boxed Warning and Warnings and Precautions (5.1) ] Vascular events [see Warnings and Precautions (5.1) ] Liver disease [see Warnings and Precautions (5.3) ] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache 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 clinical trial that evaluated the safety and efficacy of Simpesse was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18 to 40, of whom 1,006 took at least one dose of Simpesse. Adverse Reactions Leading to Study Discontinuation: 16.3% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions ( 1% of women) leading to discontinuation were irregular and/or heavy uterine bleeding (5.9%), weight gain (2.4%), mood changes (1.5%), and acne (1%). Common Treatment-Emergent Adverse Reactions ( 5% of women): irregular and/or heavy uterine bleeding (17%), weight gain (5%), acne (5%). Serious Adverse Reactions: migraine, cholecystitis, cholelithiasis, pancreatitis, abdominal pain, and major depressive disorder. Postmarketing Experience The following adverse reactions have been identified during post-approval use of Simpesse. 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 7. DRUG INTERACTIONS No drug-drug interaction studies were conducted with Simpesse. Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Products If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: barbiturates bosentan carbamazepine felbamate griseofulvin oxcarbazepine phenytoin rifampin St. John s wort topiramate HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors : Significant changes (increase or decrease) in the plasma levels of the estrogen and progestin have been noted in some cases of co-administration of HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Antibiotics : There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Increase in Plasma Levels of Estradiol Associated with Co-Administered Drugs Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. Concomitant Use with Hepatitis C Vaccine (HCV) Combination Therapy Liver Enzyme Elevation Do not co-administer Simpesse with HCV drug combinations containing ombitasvir /paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions ( 5.4 )]. Changes in Plasma Levels of Co-Administered Drugs COCs containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. 8. 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. Women who do not breastfeed may start COCs no earlier than four to six weeks postpartum. . Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing 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 Simpesse 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 Simpesse before menarche is not indicated. . Geriatric Use Simpesse has not been studied in women who have reached menopause and is not indicated in this population. . Hepatic Impairment No studies have been conducted to evaluate the effect of hepatic disease on the disposition of Simpesse. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. [See Contraindications (4) and Warnings and Precautions (5.3) ]. . Renal Impairment No studies have been conducted to evaluate the effect of renal disease on the disposition of Simpesse. 10. OVERDOSAGE There have been no reports of serious ill effects from overdose of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea. 11. DESCRIPTION Simpesse (levonorgestrel and ethinyl estradiol tablets USP and ethinyl estradiol tablets USP) is an extended-cycle oral contraceptive consisting of 84 white tablets each containing 0.15 mg of levonorgestrel USP, a synthetic progestogen and 0.03 mg of ethinyl estradiol USP, and 7 light blue tablets containing 0.01 mg of ethinyl estradiol USP. The structural formulas for the active components are: Levonorgestrel is chemically 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl- 17-hydroxy-, (17α)-, (-)-. Ethinyl Estradiol is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-. Each white tablet contains the following inactive ingredients : croscarmellose sodium, lactose monohydrate, magnesium stearate, methylene chloride, microcrystalline cellulose, and povidone. Each light blue tablet contains the following inactive ingredients : colloidal silicon dioxide, FD&C Blue No. 1, lactose monohydrate, povidone, pregelatinized starch (maize), stearic acid, and vitamin E. USP Dissolution Test is pending. 12. 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. . Pharmacokinetics Absorption Ethinyl estradiol and levonorgestrel are absorbed with maximum plasma concentrations occurring within 2 hours after Simpesse 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 to 91. The mean plasma pharmacokinetic parameters of Simpesse following a single dose of one levonorgestrel/ethinyl estradiol combination tablet, for 84 days, in normal healthy women are reported in Table 3. Table 3: Mean Pharmacokinetic Parameters for Simpesse during Daily One Tablet Dosing for 84 Days AUC 0-24 hr (mean SD) C max (mean SD) T max (mean SD) Levonorgestrel Day 1 18.2 6.1 ng hr/mL 3 1 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 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 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 Simpesse 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 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 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 17β-OH position to form sulfate 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. The terminal elimination half-life for levonorgestrel after a single dose of Simpesse 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 Simpesse was found to be about 18 hours. Race The effect of race on the pharmacokinetics of Simpesse has not been evaluated. 13. NONCLINICAL TOXICOLOGY . Carcinogenesis, Mutagenesis, Impairment of Fertility [ See Warnings and Precautions (5.2 , 5.3 )]. 14. CLINICAL STUDIES In a 12-month, multicenter, randomized, open-label clinical trial, 1,006 women aged 18 to 40 were studied to assess the safety and efficacy of Simpesse, completing the equivalent of 8,681 28-day cycles of exposure. The racial demographic of those enrolled was: Caucasian (80%), African-American (11%), Hispanic (5%), Asian (2%), and Other (2%). There were no exclusions for body mass index (BMI) or weight. The weight range of those women treated was 91 to 360 lbs., with a mean weight of 156 lbs. Among the women in the trial, 63% were current or recent hormonal contraceptive users, 26% were prior users (who had used hormonal contraceptives in the past but not in the 6 months prior to enrollment), and 11% were new starts. Of treated women, 14.8% were lost to follow-up, 16.3% discontinued due to an adverse event, and 12.9% discontinued by withdrawing their consent. The pregnancy rate (Pearl Index [PI]) in women aged 18 to 35 years was 1.34 pregnancies per 100 women-years of use (95% confidence interval 0.54 to 2.75), based on 7 pregnancies that occurred after the onset of treatment and within 14 days after the last combination pill. Cycles in which conception did not occur, but which included the use of backup contraception, were not included in the calculation of the PI. The PI includes patients who did not take the drug correctly. 16. HOW SUPPLIED/STORAGE AND HANDLING How Supplied Simpesse tablets (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 white tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 light blue tablets each containing 0.01 mg of ethinyl estradiol. The white tablets are round, biconvex, beveled-edge, debossed with S on one side and 27 on other side. The light blue tablets are mottled, round, biconvex, beveled-edge, debossed with S on one side and 45 on other side. Pouch of 1 Extended-Cycle Wallet NDC 65862-864-94 Carton of 2 Pouches NDC 65862-864-95 Storage Conditions Store at 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature]. 17. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling Counsel patients that 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. Counsel patients that this product does not protect against HIV-infection (AIDS) and other sexually transmitted diseases. Counsel patients on Warnings and Precautions associated with COCs. Counsel patients to 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 Patient Labeling. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. Counsel patients who are breastfeeding or who desire to breastfeed that COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established. Counsel any patient who starts COCs postpartum, and who has not yet had a period, to use an additional method of contraception until she has taken a white tablet for 7 consecutive days. Counsel patients that amenorrhea may occur. Pregnancy should be considered in the event of amenorrhea, and should be ruled out if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness. Manufactured for: Aurobindo Pharma USA, Inc. 2400 Route 130 North Dayton, NJ 08810 Manufactured by: Aurobindo Pharma Limited Unit-VII (SEZ) Mahaboob Nagar (Dt)-509302 India Revised: 08/2017 FDA-Approved Patient Labeling Guide for Using Simp smart move
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