levonorgestrel oral/ethinylestradiol (Altavera, Amethia, 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)

Dosing and uses of Alesse, Triphasil (levonorgestrel-ethinyl-estradiol)

• Adult
• Pediatric

 

Adult dosage forms and strengths

levonorgestrel/ethinyl estradioL

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

• 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, 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)

• 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

 

Pediatric dosage forms and strengths

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

 

Alesse, Triphasil (levonorgestrel-ethinyl-estradiol) adverse (side) 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)

 

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

 

Contraindications

Documented hypersensitivity

Current or previous breast cancer

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

Estrogen-dependent neoplasia

Liver disease, liver tumors

Undiagnosed abnormal vaginal bleeding

Uncontrolled hypertension

Diabetes mellitus with vascular involvement

Jaundice with previous oral contraceptive use

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

Renal insufficiency, hepatic dysfunction, adrenal insufficiency, smoking >15 cigarettes/day at age >35 years (Yasmin)

Major surgery with prolonged immobilization

Cerebrovascular or coronary artery disease (current or past history)

Thrombogenic rhythm disorders

Hereditary or acquired thrombophilias

Headaches with focal neurological symptoms such as aura

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

Undiagnosed abnormal genital bleeding

Cholestatic jaundice of pregnancy or jaundice with prior pill use

 

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)

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

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

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

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

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

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

 

Pregnancy and lactation

Pregnancy category: X

Lactation: Small amounts of steroids are excreted in breast milk; estrogens may reduce quality or quantity of milk; use of other forms of birth control may be advisable until infant is fully weaned (American Academy of Pediatrics committee states that formulation is compatible with nursing)

 

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.

 

Pharmacology of Alesse, Triphasil (levonorgestrel-ethinyl-estradiol)

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