Levonorgestrel / Ethinyl Estradiol And Ethinyl Estradiol

Introduction Overview

Generic Name

levonorgestrel / ethinyl estradiol and ethinyl estradiol

Brand Name

Jaimiess

Dosage Form

Extended-cycle oral contraceptive tablets (film-coated tablets)

Drug Class

Contraceptives

Pharmacokinetics

Absorption:
Levonorgestrel and ethinyl estradiol are rapidly absorbed following oral administration, with maximum plasma concentrations reached within approximately 1.3 to 1.6 hours post-dose. Levonorgestrel demonstrates near 100% bioavailability, indicating complete absorption without significant first-pass metabolism. In contrast, ethinyl estradiol has an approximate bioavailability of 43% due to substantial first-pass metabolism occurring primarily in the gut mucosa and liver.
Clinical pharmacokinetic studies show that exposure to both steroids on Day 21 (typical 3-week regimen endpoint) and Day 84 (end of extended-cycle regimen) are comparable, with no further accumulation noted during the subsequent ethinyl estradiol-only dosing (Days 84 to 91). The effect of food intake on absorption has not been evaluated.

Distribution:
The apparent volume of distribution is approximately 1.8 L/kg for levonorgestrel and 4.3 L/kg for ethinyl estradiol, reflecting moderate tissue distribution. Levonorgestrel exhibits high plasma protein binding (97.5%–99%), primarily to sex hormone-binding globulin (SHBG) and to albumin to a lesser extent. Ethinyl estradiol binds 95%–97% to serum albumin but does not bind to SHBG. Notably, ethinyl estradiol induces SHBG synthesis, indirectly modulating levonorgestrel plasma levels by reducing its clearance.
Repeated daily administration results in greater than predicted levonorgestrel accumulation, attributed to SHBG induction and potential hepatic metabolic changes.

Metabolism:
Levonorgestrel undergoes extensive phase II metabolism primarily by conjugation at the 17β-hydroxyl position yielding sulfate and glucuronide conjugates. Secondary metabolism involves reduction to tetrahydrolevonorgestrel metabolites with subsequent conjugation and excretion. Inter-individual variability in hepatic metabolic clearance contributes significantly to levonorgestrel plasma concentration variability.
Ethinyl estradiol's metabolism involves initial conjugation to ethinyl estradiol-3-sulfate within the gut wall, followed by hepatic hydroxylation predominantly via cytochrome P450 3A4 (CYP3A4) at the 2-position, along with minor hydroxylations at 4-, 6-, and 16-positions. These hydroxylated metabolites undergo further methylation and conjugation. Variability in CYP3A4 activity impacts ethinyl estradiol metabolic rates significantly.

Elimination:
Levonorgestrel and its metabolites are excreted approximately 45% via urine and 32% via feces predominantly as glucuronide conjugates. The terminal half-life averages about 34 hours following single-dose administration.
Ethinyl estradiol is eliminated as conjugates via urine and feces, undergoing enterohepatic recirculation, with an elimination half-life of approximately 18 hours.

Race:
Pharmacokinetic differences related to racial or ethnic groups have not been studied or established for Jaimiess.

Dosage Forms

Available Dosage Forms:
Jaimiess is formulated as an extended-cycle oral contraceptive pack containing two types of tablets: 84 peach film-coated tablets and 7 yellow film-coated tablets.
- Peach tablets: each contains 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol. These are round, 6 mm in diameter, film-coated, debossed with "SZ" on one side and "J4" on the other.
- Yellow tablets: each contains 0.01 mg ethinyl estradiol. These are round, 5 mm in diameter, film-coated, debossed with "SZ" on one side and "L1" on the other.
The pack provides a 13-week (91-day) supply of tablets designed for extended-cycle contraception.

Dosages for Adults and Adolescents:
The dosing regimen consists of taking one peach tablet daily for 84 consecutive days, followed by one yellow tablet daily for 7 days, completing a 91-day cycle. This administration is continuous, with no tablet-free intervals between cycles. The tablets must be taken at the same time every day to maximize contraceptive efficacy, ideally within the same hour each day.
Patients should start the first cycle on the first Sunday after onset of menstruation, or on the day menstruation begins if that day is Sunday. Subsequent cycles start the day after the last yellow tablet of the previous pack.

Specific Patient Populations:
- Adolescents (postpubertal): Safe and effective use is expected as in adults.
- Postpartum women: Start no earlier than 4 weeks after delivery if not breastfeeding; back-up contraception is needed until tablets have been taken for 7 consecutive days.
- Women switching from other contraceptives: Start on the Sunday following cessation of the previous method; use backup contraception for 7 days.
- Women after abortion/miscarriage: Timing depends on trimester; for first trimester, start on the Sunday after the procedure; for second trimester, wait 4 weeks before starting to reduce thromboembolic risk.

Missed doses instructions are clearly defined by the number of tablets missed, with advices to use back-up contraception for specified periods.

Storage:
Store at controlled room temperature 20°C to 25°C (68°F to 77°F), with permitted excursions from 15°C to 30°C (59°F to 86°F).

Mechanism Of Action

Jaimiess is a combination oral contraceptive containing levonorgestrel, a synthetic progestin, and ethinyl estradiol, a synthetic estrogen. The primary mechanism by which Jaimiess prevents pregnancy is the suppression of ovulation. This is achieved through the synergistic interaction of its hormonal components on the hypothalamic-pituitary-ovarian axis.

Levonorgestrel exerts negative feedback on the hypothalamus and pituitary gland, leading to inhibition of gonadotropin-releasing hormone (GnRH) secretion and a consequent decrease in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. This suppression prevents the mid-cycle LH surge that triggers ovulation. Concurrently, ethinyl estradiol stabilizes the endometrial lining and contributes to the suppression of follicular development by enhancing negative feedback mechanisms on the pituitary.

At the cellular level, levonorgestrel binds to progesterone receptors in the hypothalamus and pituitary, altering gene expression and neurotransmitter release to decrease gonadotropin production. Ethinyl estradiol binds to estrogen receptors, modulating the transcription of genes involved in hormonal feedback loops and increasing the synthesis of sex hormone-binding globulin (SHBG), which reduces levels of free and bioactive androgens like levonorgestrel.

Additionally, the hormones induce changes in cervical mucus, making it thicker and less permeable to sperm penetration, thereby reducing fertilization likelihood. They also induce endometrial alterations that may hinder implantation of a fertilized ovum, though this is a secondary mechanism. These pharmacodynamic actions collectively provide reliable contraception.

Compared to similar combination oral contraceptives, Jaimiess delivers levonorgestrel and ethinyl estradiol in an extended-cycle fashion, offering prolonged hormone exposure per year (more weeks of hormone dosing compared to monthly regimens), which may lead to extended suppression of ovulation and reduction in the frequency of menstrual bleeding episodes.

Clinical studies have demonstrated that when taken exactly as prescribed, Jaimiess achieves a low Pearl Index, indicating high contraceptive efficacy through these mechanisms of action.

Pharmacological Actions

Suppression of ovulation through inhibition of the hypothalamic-pituitary-ovarian axis.
Thickening of cervical mucus to inhibit sperm penetration and motility.
Induction of endometrial changes that reduce the likelihood of implantation.
Alteration of cervical mucus viscosity via progestin action.
Increase in sex hormone-binding globulin levels mediated by ethinyl estradiol, reducing free androgen levels.
Regulation of menstrual cycles via hormonal stabilization of endometrium.
Modulation of gonadotropin secretion resulting in anovulation.
Extended-cycle dosing provides sustained suppression of reproductive hormones and reduces menstrual frequency.
Minimal metabolic enzymatic interaction altering plasma hormone levels through CYP3A4 involvement.
Estrogenic component modulates hepatic protein synthesis affecting coagulation factors.

Therapeutic Or Clinical Uses

Primary use in prevention of pregnancy in females of reproductive potential.
Extended-cycle oral contraception to reduce menstrual frequency.
Contraceptive option for women seeking a 91-day dosing cycle regimen.
Allows regulation of menstrual bleeding patterns and reduction of dysmenorrhea associated with menstruation.
Suitable for women preferring oral contraceptive methods with established efficacy.
Alternative contraceptive choice for women without contraindications to combined hormonal contraceptives.
Use in females aged 18-40 years with proven safety and efficacy.
Contraceptive option for patients transitioning from other hormonal methods requiring continuous hormone administration.
May be considered in women who desire fewer withdrawal bleedings per year.
Prevention of ovulation in women with menstrual irregularities when contraception is desired.

Side Or Adverse Effects

Irregular and/or heavy uterine bleeding (≥5%).
Weight gain (reported in approximately 5% of users).
Acne flare or new-onset acne (≥5%).
Mood changes including depression and mood swings (reported as a cause for discontinuation in ~1.5%).
Headache and migraine, with increased frequency or severity in some users.
Nausea and gastrointestinal disturbances including vomiting and abdominal discomfort.
Breast tenderness and changes in breast tissue.
Decreased libido or sexual desire in some women.
Fluid retention and bloating.
Chloasma or pigmentation changes, particularly with sun exposure.
Hypertension or elevation in blood pressure.
Gallbladder disease or exacerbation of pre-existing conditions.
Risk of venous thromboembolism including deep vein thrombosis and pulmonary embolism.
Rare hepatic adverse events including liver tumors and elevated liver enzymes.
Potential for rare but serious cardiovascular events such as myocardial infarction or stroke in susceptible populations.

Precautions

Careful assessment of cardiovascular risk factors prior to initiation, especially in women over 35 or who smoke.
Monitoring for signs and symptoms of thromboembolic events; discontinue if such events occur.
Closely monitor blood pressure during therapy, particularly in hypertensive patients.
Evaluate unexplained vaginal bleeding for differential diagnoses including malignancy.
Caution in women with pre-existing gallbladder disease due to possible worsening.
Monitor glucose levels in prediabetic and diabetic women; consider alternative methods in uncontrolled diabetes.
Assess metabolic lipid profiles in women with dyslipidemia; switch contraceptives if adverse changes occur.
Observe mental health status in patients with history of depression; discontinue if depression recurs or worsens.
Advise women with hereditary angioedema about potential exacerbation of symptoms.
Avoid use in patients with acute or decompensated liver disease.
Advise sun protection measures in women prone to chloasma who use this product.
Use backup contraception during co-administration of CYP3A4 enzyme inducers.
Educate about potential for reduced milk production in breastfeeding women; recommend alternative methods.
Advise prompt medical evaluation for symptoms such as severe headaches, visual disturbances, or chest pain.
Caution in patients with migraines, especially with aura or over age 35.

Warnings

Boxed warning regarding increased risk of serious cardiovascular events, including myocardial infarction and stroke, especially in women over 35 who smoke.
Contraindication in women with a history or high risk of arterial or venous thrombotic events.
Risk of thromboembolism is highest during the first year of use and after restarting following a break of 4 weeks or more.
Discontinue at least 4 weeks prior to major surgery and resume no sooner than 2 weeks postoperatively.
Not recommended for use in postpartum women until 4 weeks after delivery due to thromboembolic risk.
Risk of elevated liver enzymes and serious liver injury when combined with certain Hepatitis C drug regimens; contraindicated use with ombitasvir/paritaprevir/ritonavir-containing regimens.
Warning for possible enhanced risk of benign and malignant liver tumors; rupture of hepatic adenomas may be fatal.
Possible increased blood pressure requiring monitoring; discontinue if significant elevation occurs.
Potential for breakthrough bleeding and spotting, especially during early treatment cycles.
May cause loss of visual acuity or ocular lesions; evaluate immediately if visual disturbances occur.
Potential increased risk of breast cancer with current or recent prolonged use, although epidemiological evidence is mixed.
Not protective against HIV or other sexually transmitted infections.
Potential elevation of thyroid-binding and cortisol-binding globulins, necessitating dose adjustments of replacement therapies.
Possible exacerbation of hereditary angioedema symptoms.
Risk of chloasma; patients should avoid direct sunlight exposure.

Contraindication

Women over 35 years old who smoke cigarettes.
Current or history of arterial or venous thrombotic/thromboembolic disorders including deep vein thrombosis, pulmonary embolism, cerebrovascular accident, myocardial infarction.
Known thrombogenic valvular or rhythm heart diseases such as subacute bacterial endocarditis with valvular disease or atrial fibrillation.
Inherited or acquired hypercoagulopathies.
Uncontrolled hypertension or hypertension with vascular disease.
Diabetes mellitus with vascular disease, nephropathy, retinopathy, neuropathy, or diabetes duration exceeding 20 years.
Migraine headaches with focal neurological symptoms or aura, or any migraine if over age 35.
Current or history of breast cancer, especially hormone-sensitive types.
Acute viral hepatitis, severe (decompensated) cirrhosis, or benign or malignant liver tumors.
Undiagnosed abnormal uterine bleeding.
Concomitant use with Hepatitis C virus drug combinations containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir due to risk of ALT elevations.

Drug Interactions

Metabolic enzyme inducers (e.g., barbiturates, carbamazepine, phenytoin, rifampin, St. John's wort) can decrease plasma concentrations of levonorgestrel and ethinyl estradiol, potentially reducing contraceptive effectiveness and increasing breakthrough bleeding.
Colesevelam coadministration reduces systemic exposure of ethinyl estradiol; dosing separation by at least 4 hours is recommended.
CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, ketoconazole, and grapefruit juice may increase plasma concentrations of contraceptive hormones.
Certain HIV and hepatitis C protease inhibitors and non-nucleoside reverse transcriptase inhibitors may decrease or increase systemic estrogen and progestin exposure, affecting contraceptive efficacy.
Levonorgestrel and ethinyl estradiol may decrease plasma levels of lamotrigine, potentially reducing seizure control.
Concomitant use with thyroid hormone or corticosteroid replacement therapy may increase binding globulin levels, necessitating dose adjustments.
Contraceptive hormones can alter pharmacokinetics of drugs such as acetaminophen, morphine, salicylic acid, temazepam, cyclosporine, prednisolone, and theophylline.
Use of Hepatitis C drug regimens containing ombitasvir/paritaprevir/ritonavir is contraindicated due to risk of significant liver enzyme elevations.
Use with glecaprevir/pibrentasvir is not recommended owing to potential ALT elevations.
Enzyme inducers require backup contraception during use and for 28 days after discontinuation.
Co-administration with atorvastatin or rosuvastatin may increase ethinyl estradiol levels by 20–25%.
Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol.
Interactions with protease inhibitors vary, requiring careful monitoring.
Potential drug interaction leading to altered metabolism and efficacy underscores the need for thorough medication review.

Preparations Of The Drug

Extended-Cycle Tablet Dispensers containing 91 tablets per pack.
84 peach film-coated tablets each containing 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol.
7 yellow film-coated tablets each containing 0.01 mg ethinyl estradiol.
Peach tablets: round, 6 mm diameter, debossed with 'SZ' on one side and 'J4' on the other side.
Yellow tablets: round, 5 mm diameter, debossed with 'SZ' on one side and 'L1' on the other side.
Inactive ingredients in peach tablets include anhydrous lactose, iron oxides (black, red, yellow), magnesium stearate, povidone, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
Inactive ingredients in yellow tablets include iron oxide yellow, lactose monohydrate, lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc, titanium dioxide, and xanthan gum.
Manufactured by Laboratorios Leon Farma S.A., Spain.
Packaged and labeled for Xiromed, LLC, Florham Park, NJ.
Store at controlled room temperature 20°C to 25°C (68°F to 77°F).
Product type: prescription-only hormonal contraceptive tablets.
Available as ANDA-approved generic products.
Pack design facilitates adherence to extended-cycle regimen with clear identification of pill sequence.