Get your patient on Jaimiess - Levonorgestrel / Ethinyl Estradiol And Ethinyl Estradiol (Levonorgestrel / Ethinyl Estradiol And Ethinyl Estradiol)

Begin Jaimiess on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the first peach tablet that day.

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

1. Start the first peach tablet on the first Sunday after onset of menstruation. Then take one peach tablet daily for 84 consecutive days. Use a non-hormonal back-up method of contraception (such as condoms and spermicide) until a peach tablet has been taken daily for 7 consecutive days.
2. Then take one yellow tablet for 7 consecutive days. Bleeding should occur during the 7 days that the yellow 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 Jaimiess, following the same schedule: 84 days taking a peach tablet followed by 7 days taking a yellow 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 peach tablet daily for 7 consecutive days.

Switching to Jaimiess 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 peach tablet for 7 consecutive days.

Starting Jaimiess after Abortion or Miscarriage

First-trimester

Jaimiess 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 peach 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 Jaimiess 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 peach tablet for 7 consecutive days [see Contraindications (4 ) and Warnings and Precautions (5.1 )].

Starting Jaimiess after Childbirth

Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Jaimiess 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 peach 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 Jaimiess [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 Jaimiess is one peach tablet daily for 84 consecutive days, followed by one yellow tablet daily for 7 days. To achieve maximum contraceptive effectiveness, Jaimiess 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 JAIMIESS Tablets

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

Risk Summary

There is no use for contraception in pregnancy; therefore, Jaimiess 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.

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 woman 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 levonorgestrel and ethinyl estradiol tablets, and ethinyl estradiol tablets before menarche is not indicated.

Jaimiess has not been studied in postmenopausal women and is not indicated in this population.

No studies have been conducted to evaluate the effect of hepatic disease on the disposition of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. However, steroid hormones may be poorly metabolized in patients with impaired liver function. 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 )].

• Stop Jaimiess if an arterial or deep venous thrombotic/thromboembolic event occurs.

• Stop Jaimiess if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately.

• Discontinue Jaimiess during prolonged immobilization. If feasible, stop Jaimiess at least 4 weeks before and through 2 weeks after major surgery, or other surgeries known to have an elevated risk of thromboembolism.
• Start Jaimiess 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 Jaimiess evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Jaimiess 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.

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 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 levonorgestrel and ethinyl estradiol tablets, and ethinyl estradiol tablets 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).

Elevated Liver Enzymes

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

Liver Tumors

Levonorgestrel and ethinyl estradiol tablets, and ethinyl estradiol tablets are contraindicated in women 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 women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4 )] . For all women, 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 women 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 levonorgestrel and ethinyl estradiol tablets, and ethinyl estradiol tablets. 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.

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 women who are taking levonorgestrel and ethinyl estradiol tablets, and ethinyl estradiol tablets.

Dyslipidemia

Consider alternative contraception for women with uncontrolled dyslipidemia. Levonorgestrel and ethinyl estradiol tablets, and ethinyl estradiol tablets may cause adverse lipid changes.

Women 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

Women 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 unscheduled 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 primary clinical trial (PSE-301) that evaluated the efficacy of levonorgestrel and ethinyl estradiol tablets, and ethinyl estradiol tablets 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 levonorgestrel and ethinyl estradiol tablets, and ethinyl estradiol tablets, 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

Table 3: Total Number of Days with Unscheduled Spotting

Figure 2 shows the percentage of levonorgestrel and ethinyl estradiol tablets, and ethinyl estradiol tablets 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 Levonorgestrel and Ethinyl Estradiol Tablets, and Ethinyl Estradiol Tablets 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 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 women 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 women with a history of chloasma gravidarum. Advise women 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.

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 was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18-40, of whom 1,006 took at least one dose of levonorgestrel and ethinyl estradiol tablets, and ethinyl estradiol.

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 (1.0%).

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.

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 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 levonorgestrel and ethinyl estradiol tablets, and ethinyl estradiol. 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 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 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).

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

Table 5: Significant Drug Interaction Information for Drugs Co-Administered With COCs

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 Warning 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.

COCs prevent pregnancy primarily by suppressing ovulation.

Absorption

Ethinyl estradiol and levonorgestrel are absorbed with maximum plasma concentrations occurring within 2 hours after levonorgestrel and ethinyl estradiol, and ethinyl estradiol 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 levonorgestrel and ethinyl estradiol, and ethinyl estradiol 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 Levonorgestrel and Ethinyl Estradiol, and Ethinyl Estradiol during Daily One Tablet Dosing for 84 Days

The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Jaimiess 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 levonorgestrel and ethinyl estradiol, and ethinyl estradiol 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 levonorgestrel after a single dose of levonorgestrel and ethinyl estradiol and ethinyl estradiol was found to be about 18 hours.

Race

The effect of race on the pharmacokinetics of Jaimiess has not been evaluated.

[See Warnings and Precautions (5.2 , 5.11 )].