levonorgestrel oral/ethinyl estradiol (Rx)

Brand and Other Names:Altavera, Amethia, more...Amethia Lo, Amethyst, Ashlyna, Aubra, Aviane, Camrese, Camrese Lo, Chateal, Daysee, Elifemme, Enpresse, Falmina, Introvale, Jolessa, Kurvelo, Lessina 21, Lessina 28, Levonest, Levora, LoSeasonique, Lybrel, Marlissa, Microgynon, Nordette, Orsythia, Ovranette, Portia 21, Portia 28, Quasense, Quartette, Sronyx, Trivora 28, Seasonale, Seasonique, Setlakin, Lutera, Myzilra, FaLessa, FaLessa Kit, Delyla, Fayosim, Larissia, Lillow, Rivelsa, Vienva
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

levonorgestrel/ethinyl estradiol

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

  • Days 1-21: 0.1mg/20mcg
  • 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: 0.15mg/30mcg
  • Days 22-28: Inert tablets

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

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

tablet, 91-day (Seasonique, Amethia, Ashlyna, Camrese, Daysee)

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

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

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

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

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

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

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

tablet, continuous cycle

  • 0.09mg/20mcg

Contraception

Monophasic

  • 1 active tablet PO daily for 21 days, then 1 inert tablet PO 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 (eg, 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

Safety and efficacy are expected to be the same in postpubertal adolescents aged <16 years and users aged >16 years

Use before menarche is not indicated

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Interactions

Interaction Checker

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            Adverse Effects

            Frequency Not Defined

            Amenorrhea

            Arterial thromboembolism

            Benign or malignant neoplasm of liver

            Bloating

            Breakthrough bleeding

            Breast changes (enlargement, tenderness, secretion)

            Cerebral hemorrhage

            Cerebral thrombosis

            Disorder of gallbladder

            Disorder of menstruation

            Headache

            Hypertension

            Mood swings

            Myocardial infarction

            Nausea and vomiting

            Pulmonary embolism (PE)

            Scanty vaginal bleeding

            Stomach cramps

            Thrombophlebitis

            Weight change (increased or decreased)

            Postmarketing Reports

            Pancreatitis

            Cholestatic jaundice

            Retinal vein thrombosis

            Hirsutism

            Erythema multiforme

            Erythema nodosum

            Hemorrhagic eruption

            Melasma/chloasma

            Migraine

            Urticaria

            Angioedema

            Respiratory

            Circulatory symptoms

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            Warnings

            Black Box Warnings

            Cigarette smoking & risk of cardiovascular disease

            • Cigarette smoking increases risk of serious cardiovascular adverse effects from combination hormonal contraceptive use
            • Risk increases with age (>35 years) and with heavy smoking (≥15 cigarettes/day)
            • Advise women who use hormonal oral contraceptives not to smoke
            • Not for the treatment of patients who use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations

            Contraindications

            Documented hypersensitivity

            Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past

            Arterial thromboembolic disease (stroke, myocardial infarction [MI]), thrombophlebitis, deep vein thrombosis (DVT)/PE, thrombogenic valvular disease

            Estrogen-dependent neoplasia

            Liver tumors, benign or malignant, or liver disease

            Undiagnosed abnormal vaginal bleeding

            Uncontrolled hypertension

            Diabetes mellitus and over age 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of >20 years duration

            Inherited or acquired hypercoagulopathies, smokers aged >35 years (Natazia)

            Renal insufficiency, hepatic dysfunction, adrenal insufficiency

            Headaches with focal neurological symptoms or have migraine headaches with aura

            Women >35 with any migraine headaches

            Smoking >15 cigarettes/day at age >35 years

            Major surgery with prolonged immobilization

            Cerebrovascular or coronary artery disease (current or past history)

            Thrombogenic rhythm disorders

            Hereditary or acquired thrombophilias

            Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia

            Undiagnosed abnormal vagina/uterine bleeding

            Cholestatic jaundice of pregnancy or jaundice with prior pill use

            Receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir

            Cautions

            Use caution in patients with family history of breast cancer, DVT/PE, or both; current or previous depression, endometriosis, diabetes mellitus, hypertension, bone mineral density changes, renal or hepatic impairment, bone metabolic disease, systemic lupus erythematosus (SLE); conditions exacerbated by fluid retention (eg, migraine, asthma, epilepsy)

            Risk of VTE is highest during first year of use of a COCs and when restarting oral contraception after a break of 4 weeks or longer; risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued; use of COCs increases risk of arterial thromboses that result in strokes and myocardial infarctions, especially in women with other risk factors for these events; COCs have been shown to increase both relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes); risk increases with age, particularly in women over 35 years of age who smoke

            Discontinue therapy if an arterial thrombotic event or venous thromboembolic (VTE) event occurs; if feasible, stop therapy at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during and following prolonged immobilization; initiate therapy no earlier than 4 weeks after delivery in women who are not breastfeeding; risk of postpartum VTE decreases after third postpartum week, whereas risk of ovulation increases after third postpartum week

            Discontinue if the following develop: Jaundice, visual problems (may cause contact lens intolerance), any signs of VTE, migraine with unusual severity, significant blood pressure increase, severe depression, increased risk of thromboembolic complications after surgery

            Discontinue 4 weeks before major surgery or prolonged immobilization

            Discontinue drug prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; therapy can be restarted approximately 2 weeks following completion of treatment with the hepatitis C combination drug regimen

            Use of warfarin or other oral anticoagulants (increase in anticoagulant dose may be warranted)

            Estrogen component of COCs may raise serum concentrations of thyroxine-binding globulin, sex hormone- binding globulin, and cortisol-binding globulin; dose of replacement thyroid hormone or cortisol therapy may need to be increased

            Some studies link oral contraceptive use with increased risk of breast cancer, whereas others do not; risk depends on conditions where naturally high hormone levels persist for long periods, including early-onset menstruation (age <12 years), late-onset menopause (age >55 years), first child after age 30 years, nulliparity

            Increased risk of cervical cancer with oral contraceptive use, however, human papillomavirus (HPV) remains primary risk factor for this cancer

            Discontinue hormonal therapy prior to starting therapy with combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; may restart approximately 2 weeks following completion of treatment with combination drug regimen

            Long-term (≥5 years) use of oral contraceptives may be associated with increased risk

            Increased risk of liver cancer with oral contraceptive use; risk increases with duration of use

            CDC guidelines recommend waiting ≥3 weeks after vaginal birth or ≥6 weeks after cesarean section to decrease risk of VTE before initiating combined hormonal contraceptives; women with additional risk factors for VTE (besides postpartum status) should not use combined hormonal contraceptives

            Scheduled withdrawal bleeding does not occur with therapy; the absence of withdrawal bleeding cannot be used as a sign of an unexpected pregnancy and as such, unexpected pregnancy may be difficult to recognize; if pregnancy suspected, a pregnancy test should be performed

            Benign hepatic adenomas are associated with oral contraceptive use; rupture of rare, benign, hepatic adenomas may cause death through intraabdominal hemorrhage

            Retinal thrombosis associated with use of oral contraceptives that may lead to partial or complete loss of vision reported; oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions; appropriate diagnostic and therapeutic measures should be undertaken immediately

            Increased risk of myocardial infarction attributed to oral contraceptive use; risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes

            An increased risk of venous thromboembolic and thrombotic disease associated with use of oral contraceptives is well established; the excess risk is highest during the first year a woman ever uses a combined oral contraceptive

            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 receiving therapy

            Oral contraceptives have been shown to increase both relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, risk is greatest among older (>35 years), hypertensive women who also smoke

            Not for use in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver; acute or chronic disturbances of liver function may necessitate discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded; discontinue therapy if jaundice develops

            Women with migraine (particularly migraine/ headaches with focal neurological symptoms such as aura) who take combination oral contraceptives may be at increased risk of stroke

            A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease

            A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents; a decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease; women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives; some progestogens may elevate LDL levels and may render control of hyperlipidemias more difficult; nonhormonal contraception should be considered in women with uncontrolled dyslipidemias; persistent hypertriglyceridemia may occur; elevations of plasma triglycerides may lead to pancreatitis and other complications

            Diarrhea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations

            Increase in blood pressure reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use; women with history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception; if women with hypertension elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued

            Onset or exacerbation of migraine or development of headache with new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause

            The convenience of having no scheduled menstrual bleeding should be weighed against the inconvenience of unscheduled breakthrough bleeding and spotting

            Ectopic as well as intrauterine pregnancy may occur in contraceptive failures

            Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care

            For women with well-controlled hypertension, monitor blood pressure and stop treatment if blood pressure rises significantly

            Studies suggest a small increased relative risk of developing gallbladder disease among COC users; use of COCs may worsen existing gallbladder disease; a past history of COC-related cholestasis predicts an increased risk with subsequent COC use; women with a history of pregnancy-related cholestasis may be at increased risk for COC related cholestasis

            If a woman receiving therapy develops new headaches that are recurrent, persistent, or severe, evaluate cause and discontinue therapy if indicated; consider discontinuation in case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event)

            If bleeding persists or occurs after previously regular cycles, 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 contraceptive product

            Women receiving therapy may experience amenorrhea, absence of withdrawal bleeding, even if they are not pregnant; if scheduled (withdrawal) bleeding does not occur, consider possibility of pregnancy if patient has not adhered to prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have); consider possibility of pregnancy at time of first missed period and take appropriate diagnostic measures; if patient has adhered to prescribed regimen and misses two consecutive periods, rule out pregnancy

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            Pregnancy & Lactation

            Pregnancy

            There is little or no increased risk of birth defects in women who inadvertently use combination oral contraceptives 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 combination oral contraceptives prior to conception or during early pregnancy

            Not to be administered to induce withdrawal bleeding as a test for pregnancy; not for use during pregnancy to treat threatened or habitual abortion

            Lactation

            Advise nursing mother to use other forms of contraception, when possible, until she has weaned her child; combination oral contraceptives 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

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Levonorgestrel: Progestin; inhibits secretion of gonadotropins from pituitary; prevents follicular maturation and ovulation; stimulates growth of mammary tissues

            Ethinyl estradiol: Reduces release of luteinizing hormone-releasing hormone (LHRH) from hypothalamus; reduces release of gonadotropin from pituitary; increases synthesis of DNA, RNA, and various proteins in target tissues

            Absorption

            Bioavailability (levonorgestrel): Nearly 100%; rapidly and almost completely absorbed; not subject to first-pass metabolism; (ethinyl estradiol): 43%; rapidly and almost completely absorbed from gastrointestinal (GI) tract; subject to first-pass metabolism in gut mucosa and liver

            Distribution

            Protein bound (levonorgestrel): 97.5-99% (principally to sex hormone-binding globulin [SHBG] and, to a lesser extent, to serum albumin); (ethinyl estradiol): 95-97% (to serum albumin)

            Vd (levonorgestrel): 1.8 L/kg; (ethinyl estradiol): 4.3 L/kg

            Metabolism

            Levonorgestrel: Forms conjugated metabolites

            Ethinyl estradiol: Metabolized in liver by CYP3A4 to estriol and estrone

            Elimination

            Half-life (levonorgestrel): 22-49 hr (after single dose); (ethinyl estradiol): 12-23 hr

            Excretion (levonorgestrel and metabolites): Urine (40-68%) and feces (16-48%), mostly as glucuronide conjugates; (ethinyl estradiol): Urine and feces, as glucuronide and sulfate conjugates

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
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