levonorgestrel/ethinyl estradiol

Levonorgestrel/ethinyl estradiol is a combination hormonal contraceptive (CHC) for use by women of reproductive potential to prevent pregnancy. Levonorgestrel and ethinyl estradiol are synthetic formulations of the natural female sex hormones progesterone and estrogen respectively, and have similar effects. Oral hormonal contraceptives work by interfering with a woman’s natural hormonal balance that enables ovulation, egg fertilization, implantation and maintenance of pregnancy.

The reproductive cycle is regulated by a system known as the hypothalamic-pituitary-gonadal axis. The hypothalamus secretes gonadotropin releasing hormone (GnRH), which stimulates the pituitary gland to release follicle stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH stimulate ovulation and the production of estrogen and progesterone at the appropriate times during the cycle to enable conception and pregnancy.

Levonorgestrel/ethinyl estradiol is taken in a specific schedule that disrupts the hormonal balance required for pregnancy to occur. Levonorgestrel and ethinyl estradiol work by binding to their respective progesterone and estrogen receptors on reproductive tissues that respond to these hormones. Combination hormonal contraceptives work in the following ways to prevent pregnancy:

• Suppress ovulation and maturation of ovum by reducing the release of GnRH, also known as luteinizing-hormone releasing hormone (LHRH) from the hypothalamus, and the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland.
• Thicken the cervical mucus, hindering the passage of sperm into the uterus.
• Thin the uterus lining (endometrium) preventing implantation of the fertilized egg.

• Do not take levonorgestrel/ethinyl estradiol if you are older than 35 years and a smoker. Cigarette smoking increases the risk for serious cardiovascular adverse effects from use of combination hormonal contraceptives.
• Do not take levonorgestrel/ethinyl estradiol if you are at high risk for blood clot blocks in veins or arteries (arterial or venous thrombotic diseases). Risk factors include:
  • Age above 35 years and cigarette smoking
  • Presence or history of deep vein thrombosis or pulmonary embolism
  • Cerebrovascular disease
  • Coronary artery disease
  • Heart valve or rhythm disease that can predispose to blood clot formation, such as bacterial endocarditis with valvular disease or atrial fibrillation
  • Inherited or acquired blood clotting disorders (hypercoagulopathies)
  • Uncontrolled high blood pressure (hypertension) or hypertension with valvular disease
  • Diabetes mellitus:
    • And age over 35 years
    • Of more than 20 years of duration
    • And hypertension, vascular disease or other end-organ damage
  • Migraine headaches and age above 35 years, migraines with aura or headaches with focal neurological symptoms
• Evaluate women for risk of arterial or venous thrombotic/thromboembolic diseases before prescribing levonorgestrel/ethinyl estradiol and do not prescribe to women who have a personal or family history.
  • Stop levonorgestrel/ethinyl estradiol if an arterial or venous thrombotic or thromboembolic event occurs.
  • Stop levonorgestrel/ethinyl estradiol if a woman develops unexplained vision loss, double vision (diplopia), bulging eyes (proptosis), swelling of optic disc or retinal vascular lesions and evaluate for retinal vein thrombosis. Advise users to seek prompt medical attention if they develop such symptoms.
• Combination hormonal contraceptives (CHC) can cause liver test abnormalities and increase the risk for liver adenomas.
  • Do not prescribe levonorgestrel/ethinyl estradiol to women with liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis.
  • Discontinue levonorgestrel/ethinyl estradiol if a user develops jaundice.
  • If a woman develops liver test abnormalities, discontinue levonorgestrel/ethinyl estradiol until values return to normal and CHC is ruled out as the cause.
• Do not use levonorgestrel/ethinyl estradiol in women taking hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for liver enzyme elevations. Discontinue levonorgestrel/ethinyl estradiol before starting hepatitis C treatment and restart 2 weeks after treatment completion.
• Regularly monitor blood pressure in women with well-controlled hypertension and discontinue levonorgestrel/ethinyl estradiol if blood pressure increases significantly.
• The risk for cardiovascular diseases increases with age. Consider risk factors before prescribing levonorgestrel/ethinyl estradiol, particularly in women above 35 years of age.
• CHC may increase the risk for new onset or worsening of gallbladder disease.
• Levonorgestrel/ethinyl estradiol may reduce glucose tolerance. Monitor glucose levels in users who are prediabetic or diabetic.
• If a user develops recurrent, persistent or severe headaches, evaluate for cause and discontinue levonorgestrel/ethinyl estradiol if indicated.
• Levonorgestrel/ethinyl estradiol may cause unscheduled bleeding, especially in the first 3 months of use. If bleeding persists, evaluate for pregnancy or malignancy. Test for pregnancy if regular bleeding does not occur, although, some women may experience absence of bleeding even if not pregnant.
• Carefully monitor women with a history of depression and discontinue CHC if depression recurs to a serious degree.
• Some studies indicate CHCs are associated with an increased risk of cervical cancer or growth of abnormal cells (intraepithelial neoplasia) that can turn into cancer.
• The estrogen component of levonorgestrel/ethinyl estradiol may increase the levels of certain proteins in the blood, including thyroxine binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. Doses of replacement thyroid hormone or cortisol therapy may need to be increased.
• External source (exogenous) of estrogen may induce or exacerbate symptoms in women with hereditary angioedema, a disorder that causes recurrent swelling.
• Levonorgestrel/ethinyl estradiol use may cause dark skin patches (chloasma), particularly in women with a history of chloasma. Advise women with a history of chloasma to avoid exposure to sun or ultraviolet radiation while using CHC.

Serious side effects of levonorgestrel/ethinyl estradiol include increased risk of:

• Blood clot block (thromboembolism) in arteries or veins
• Heart attack (myocardial infarction)
• Cerebral thrombosis
• Cerebral hemorrhage
• Stroke
• High blood pressure (hypertension)
• Deep vein thrombosis (DVT)
• Pulmonary embolism (PE)
• Vein inflammation with blood clots (thrombophlebitis)
• Blood clot in the abdominal area (mesenteric thrombosis)
• Retinal thrombosis
• Benign or malignant liver tumor
• Gallbladder disease
• Cervical cancer

Common side effects of levonorgestrel/ethinyl estradiol include:

• Impaired bile flow (cholestasis)
• Liver function abnormalities
• Decreased glucose tolerance
• Increase in triglyceride levels
• Inflammation of the pancreas (pancreatitis)
• Headache
• Abdominal pain
• Nausea
• Breakthrough bleeding
• Bleeding or spotting between cycles
• Increased duration of menstrual bleeding (metrorrhagia)
• Infrequent menstrual periods (oligomenorrhea)
• Absence of menstruation (amenorrhea)
• Vaginal Candida yeast infection (moniliasis)
• Vaginal inflammation (vaginitis)
• Decrease in certain blood proteins (globulins)
• New onset or worsening of depression
• Onset or exacerbation of swelling in women with hereditary angioedema
• Elevation of liver enzymes with concurrent hepatitis C treatment
• Pain
• Acne
• Darkening of skin (melasma/chloasma)

Less common side effects of levonorgestrel/ethinyl estradiol include:

• Vomiting
• Abdominal cramps and bloating
• Changes in weight or appetite
• Fluid retention and swelling (edema)
• Cholestatic jaundice
• Decrease in serum folate levels
• Mood changes
• Libido changes
• Breast tenderness
• Breast pain
• Breast enlargement
• Increased cervical mucus
• Temporary infertility after treatment discontinuation
• Aggravation of varicose veins
• Obstruction of venous outflow tract from the liver (Budd-Chiari syndrome)
• Intolerance to contact lenses
• Steepening of corneal curvature
• Possible reduction in lactation if used immediately after childbirth
• Exacerbation of certain disorders including:
  • Systemic lupus erythematosus
  • Porphyria
  • Chorea
• Severe allergic reactions (anaphylaxis)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

Tablet, monophasic (Aubra, Aviane, Delyla, Falmina, Falessa, Falessa Kit, Larissia, Lessina, Lutera, Orsythia, Vienva)

• Days 1-21: 0.1 mg/20 mcg
• Days 22-28: Inert tablets
• Days 22-28: folic acid 1 mg (Falessa Kit)

Tablet, monophasic (Altavera, Chateal, Kurvelo, Levora, Lillow, Marlissa, Nordette, Portia)

• Days 1-21: 0.15 mg/30 mcg
• Days 22-28: Inert tablets

Tablet, 91-day (Seasonale, Quasense, Introvale, Jolessa, Setlakin)

• Days 1-84: 0.15 mg/30 mcg
• Days 85-91: Inert tablets

Tablet, 91-day (Seasonique, Amethia, Ashlyna, Camrese, Daysee, Jaimiess)

• Days 1-84: 0.15 mg/30 mcg
• Days 85-91: Ethinyl estradiol 10 mcg

Tablet, 91-day (LoSeasonique, Amethia Lo, Camrese Lo)

• Days 1-84: 0.1 mg/20 mcg
• Days 85-91: Ethinyl estradiol 10 mcg

Tablet, 91-day (Quartette, Fayosim, Rivelsa)

• Days 1-42: 0.15 mg/20 mcg
• Days 43-63: 0.15 mg/25 mcg
• Days 64-84: 0.15 mg/30 mcg
• Days 85-91: Ethinyl estradiol 10 mcg

Tablet, triphasic (Elifemme, Enpresse, Levonest, Trivora 28)

• Days 1-6: 0.05 mg/30 mcg
• Days 7-11: 0.075 mg/40 mcg
• Days 12-21: 0.125 mg/30 mcg
• Days 22-28: Inert tablets

Tablet, continuous cycle

• 0.09 mg/20 mcg

Adult:

Contraception

Monophasic

• 1 active tablet orally daily for 21 days, then 1 inert tablet orally daily for 7 days (follow manufacturer's color-coding for sequence)

91-day

• 1 combination tablet daily for 84 days, then either 1 inert tablet or 1 tablet of ethinyl estradiol 10 mcg for 7 days
• First cycle begins on first Sunday after onset of menstruation; if menstruation begins on Sunday, first combination tablet is taken that day, with subsequent tablets taken in order specified on dispenser
• Use nonhormonal backup method of contraception (e.g., condoms and spermicide) for first 7 days of treatment
• Next and all subsequent 91-day courses of tablets are initiated without interruption on same day of the week (Sunday), following same schedule, with tablets taken at same time of day on each day of active treatment

Triphasic

• Regimens vary; see package inserts (follow manufacturer's color-coding for sequence)

Continuous cycle

• 1 tablet PO daily at same time each day, with no tablet-free interval

Missed Active Contraceptive Dose

One active tablet missed

• Take 1 tablet as soon as possible, or take 2 tablets on following day
• Alternatively, take 1 tablet, discard missed tablet, and continue taking subsequent tablets as scheduled
• Use other forms of contraception for next 7 days after missed dose or until menses occur

Two active tablets missed consecutively

• Take 2 tablets as soon as remembered and continue taking as scheduled
• Alternatively, take 2 tablets daily for the next 2 days and continue taking as scheduled
• Missed 3rd week of cycle and patient is Sunday Starter: Take 1 pill every day until Sunday; discard rest of pack, and start new pack that same day
• Missed 3rd week of cycle and patient is day-1 starter: Discard rest of pack, and start new pack that same day
• Use other forms of contraception for next 7 days after missed dose or until menses occur
• Menses may not occur this month; if menses do not occur for 2 consecutive months, contact healthcare provider about possibility of pregnancy

Three active tablets missed consecutively

• Sunday starter: Take 1 pill every day until Sunday; discard rest of pack, and start new pack that same day
• Day-1 starter: Discard rest of pack, and start new pack that same day
• Use other forms of contraception for next 7 days after missed dose or until menses occur
• Menses may not occur this month; if menses do not occur for 2 consecutive months, contact healthcare provider about possibility of pregnancy

Dosing Considerations

Post pregnancy

• Increased risk of venous thromboembolism (VTE) after delivery with combined hormonal contraceptives; risk declines rapidly after 21 days but does not return to normal until 42 days after delivery
• Centers for Disease Control and Prevention (CDC) guidelines recommend waiting 3-6 weeks to initiate oral contraception in postpartum women without additional VTE risks
• After vaginal birth: Wait ≥3 weeks before initiating oral contraception
• After cesarean section birth: Wait ≥6 weeks before initiating oral contraception
• Women with other risk factors for VTE in addition to postpartum: Do not use combined hormonal contraceptives
• Presence of other VTE risk factors in addition to postpartum status: Do not use combined hormonal contraceptives

Dosing Modifications

• Renal impairment: Use with caution
• Hepatic impairment: Do not administer

Pediatric:

• Safety and efficacy are expected to be the same in postpubertal adolescents aged below 16 years and users aged above 16 years
• Use before menarche is not indicated

Overdose

Levonorgestrel/ethinyl estradiol may cause nausea and uterine bleeding in women. Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe interactions of levonorgestrel/ethinyl estradiol include:
  • fezolinetant
  • ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC)
  • tranexamic acid oral
• Levonorgestrel/ethinyl estradiol has serious interactions with at least 85 different drugs.
• Levonorgestrel/ethinyl estradiol has moderate interactions with at least 186 different drugs.
• Levonorgestrel/ethinyl estradiol has mild interactions with at least 24 different drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• Levonorgestrel/ethinyl estradiol is used for contraception and should be immediately discontinued if pregnancy takes place.
• Studies have not found an increased risk of birth defects with the use of combined hormonal contraceptives before conception or during early pregnancy.
• Contraceptive hormones and their metabolites are present in breastmilk. Hormonal contraceptives can reduce milk production, but this effect is less likely when breast-feeding is well established.
• If not breastfeeding, start levonorgestrel/ethinyl estradiol no earlier than 4 weeks after delivery. The risk of developing blood clots decreases and the likelihood of ovulation increases 3 weeks after delivery.
• When possible, use other means of contraception while breastfeeding.
• Decision to breastfeed should be based on the nursing mother’s clinical need for levonorgestrel/ethinyl estradiol, health and developmental benefits of breastfeeding, and the risks to the breastfed infant from exposure to the drug or the mother’s underlying condition.

• Take levonorgestrel/ethinyl estradiol exactly as per instructions.
• Do not take levonorgestrel/ethinyl estradiol if you are a smoker and above 35 years of age.
• Discontinue levonorgestrel/ethinyl estradiol during prolonged immobilization and for four weeks before and two weeks after any scheduled major surgery.
• Stop taking levonorgestrel/ethinyl estradiol and report immediately to your physician if you develop:
  • Any symptoms of blood clot blocks such as swelling and pain in legs, difficulty breathing or chest pain.
  • Any visual problems such as loss of vision, double vision or bulging eyes.
  • Liver-related symptoms
• Do not take levonorgestrel/ethinyl estradiol if you have:
  • Undiagnosed abnormal uterine bleeding
  • Presence or history of breast cancer or other estrogen- or progestin-sensitive cancer
• Levonorgestrel/ethinyl estradiol does not protect against transmission of human immunodeficiency virus (HIV) and other sexually transmitted diseases.
• If you have a history of developing dark skin patches (chloasma), avoid sun and ultraviolet ray exposure while taking levonorgestrel/ethinyl estradiol.
• Store levonorgestrel/ethinyl estradiol safely out of reach of children.
• In case of overdose, seek medical help or contact Poison Control.