levonorgestrel intrauterine (Rx)

Brand and Other Names:Mirena, Skyla, more...Liletta, Kyleena
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

levonorgestrel-releasing intrauterine system

  • 13.5mg/device (Skyla)
  • 19.5mg/device (Kyleena)
  • 52mg/device (Liletta, Mirena)

Contraception

Mirena

  • Initial levonorgestrel release rate is 20 mcg/day; rate reduced by 50% after 5 years
  • May remove and replace with a new unit anytime during menstrual cycle
  • Must be removed or replaced by 6 years following insertion

Skyla

  • Levonorgestrel release rate is 14 mcg/day after 24 days and 5 mcg/day after 3 years
  • May remove and replace with a new unit anytime during menstrual cycle
  • Must be removed or replaced by 3 years following insertion

Liletta

  • Initially, levonorgestrel release rate is ~20 mcg/day; rate decreases progressively to ~8.6 mcg/day after 6 yr
  • Average in vivo release rate is ~14.3 mcg/day over a period of 6 yr
  • May remove and replace with a new unit anytime during menstrual cycle
  • Must be removed or replaced by the end of sixth year following insertion

Kyleena

  • Release rate is 17.5 mcg/day after 24 days and declines to 7.4 mcg/day after 5 years
  • May remove and replace with a new unit anytime during menstrual cycle
  • Must be removed or replaced by 5 years following insertion

Heavy Menstrual Bleeding

Indicated for heavy menstrual bleeding for up to 5 years in women who choose to use intrauterine contraception as a method of contraception

Initial levonorgestrel release rate is 20 mcg/day; rate reduced by 50% after 5 years

Replace after the end of fifth year if continued treatment needed

Dosage Modifications

Renal or hepatic impairment: No studies conducted

Dosing Considerations

Starting levonorgestrel intrauterine in women not currently using hormonal or intrauterine contraception

  • Insert any time the healthcare professional assesses the woman is not pregnant
  • Consider the possibility of ovulation and conception before initiation of this product
  • If inserted during the first 7 days of the menstrual cycle or immediately after a first trimester abortion, back up contraception is not needed
  • If NOT inserted during the first 7 days of the menstrual cycle, use a barrier method of contraception or abstain from vaginal intercourse for 7 days to prevent pregnancy

Switching to intrauterine from an oral, transdermal, or vaginal hormonal contraceptive

  • Insert intrauterine device at any time
  • May be inserted during the hormone-free interval of the previous method
  • If inserted during active use of the previous method, continue that method for 7 days after intrauterine device insertion or until current treatment cycle has ended
  • If using continuous hormonal contraception, discontinue that method 7 days after insertion

Switching to levonorgestrel intrauterine from an injectable progestin contraceptive

  • May be inserted at any time
  • If inserted >3 months (13 weeks) after the last injection, use a barrier method of contraception (eg, condoms, spermicide) for 7 days after insertion

Switching to intrauterine from a contraceptive implant or another IUS

  • Insert intrauterine on the same day the implant or IUS is removed; may be insert at any time during the menstrual cycle.

Inserting intrauterine after abortion or miscarriage

  • First-trimester: May insert immediately after a first-trimester abortion or miscarriage.
  • Second-trimester: Delay inserting intrauterine until a minimum of 4 weeks (Liletta) or 6 weeks (Kyleena, Skyla, Mirena) after second-trimester abortion or miscarriage, or until the uterus is fully involuted
  • If involution is delayed, wait until involution is complete before insertion
  • If the woman has not yet had a period, consider the possibility of ovulation and conception occurring before insertion
  • Insert at any time the healthcare professional assesses woman is not pregnant
  • If not inserted during the first 7 days of the menstrual cycle, use a barrier method of contraception or abstain the patient from vaginal intercourse for 7 days after insertion to prevent pregnancy

Inserting after childbirth

  • Delay insertion until a minimum of 4 weeks (Liletta) or 6 weeks (Kyleena, Skyla, Mirena) after delivery, or until the uterus is fully involuted
  • If involution is delayed, wait until involution is complete before insertion
  • If woman has not yet had a period, consider the possibility of ovulation and conception occurring before insertion
  • May be inserted any time the healthcare professional assesses the woman is not pregnant
  • If not inserted during the first 7 days of the menstrual cycle, use a barrier method of contraception or abstain from vaginal intercourse for 7 days after insertion to prevent pregnancy
  • Increased risk of perforation in lactating women

Dosage Forms & Strengths

levonorgestrel-releasing intrauterine system

  • 13.5mg/device (Skyla)
  • 19.5mg/device (Kyleena)
  • 52mg/device (Liletta, Mirena)

Contraception

Postpubertal females

  • Skyla
    • Levonorgestrel release rate is 14 mcg/day after 24 days and 5 mcg/day after 3 years
    • May remove and replace with a new unit anytime during menstrual cycle
    • Must be removed or replaced by 3 years following insertion
  • Liletta
    • Initially, levonorgestrel release rate is ~20 mcg/day; rate decreases progressively to ~8.6 mcg/day after 6 yr
    • Average in vivo release rate is ~14.3 mcg/day over a period of 6 yr
    • May remove and replace with a new unit anytime during menstrual cycle
    • Must be removed or replaced by the end of sixth year following insertion
  • Mirena
    • Initial levonorgestrel release rate is 20 mcg/day; rate reduced by 50% after 5 years
    • May remove and replace with a new unit anytime during menstrual cycle
    • Must be removed or replaced by 5 years following insertion
  • Kyleena
    • Release rate is 17.5 mcg/day after 24 days and declines to 7.4 mcg/day after 5 years
    • May remove and replace with a new unit anytime during menstrual cycle
    • Must be removed or replaced by 5 years following insertion

Dosage Modifications

Renal or hepatic impairment: No studies conducted

Dosing Considerations

Starting levonorgestrel intrauterine in women not currently using hormonal or intrauterine contraception

  • Insert any time the healthcare professional assesses the woman is not pregnant
  • Consider the possibility of ovulation and conception before initiation of this product
  • If inserted during the first 7 days of the menstrual cycle or immediately after a first trimester abortion, back up contraception is not needed
  • If NOT inserted during the first 7 days of the menstrual cycle, use a barrier method of contraception or abstain from vaginal intercourse for 7 days to prevent pregnancy

Switching to intrauterine from an oral, transdermal, or vaginal hormonal contraceptive

  • Insert intrauterine device at any time
  • May be inserted during the hormone-free interval of the previous method
  • If inserted during active use of the previous method, continue that method for 7 days after intrauterine device insertion or until current treatment cycle has ended
  • If using continuous hormonal contraception, discontinue that method 7 days after insertion

Switching to levonorgestrel intrauterine from an injectable progestin contraceptive

  • May be inserted at any time
  • If inserted >3 months (13 weeks) after the last injection, use a barrier method of contraception (eg, condoms, spermicide) for 7 days after insertion

Switching to intrauterine from a contraceptive implant or another IUS

  • Insert intrauterine on the same day the implant or IUS is removed; may be insert at any time during the menstrual cycle.

Inserting intrauterine after abortion or miscarriage

  • First-trimester: May insert immediately after a first-trimester abortion or miscarriage.
  • Second-trimester: Delay inserting intrauterine until a minimum of 4 weeks (Liletta) or 6 weeks (Kyleena, Skyla, Mirena) after second-trimester abortion or miscarriage, or until the uterus is fully involuted
  • If involution is delayed, wait until involution is complete before insertion
  • If the woman has not yet had a period, consider the possibility of ovulation and conception occurring before insertion
  • Insert at any time the healthcare professional assesses woman is not pregnant
  • If not inserted during the first 7 days of the menstrual cycle, use a barrier method of contraception or abstain the patient from vaginal intercourse for 7 days after insertion to prevent pregnancy

Inserting after childbirth

  • Delay insertion until a minimum of 4 weeks (Liletta) or 6 weeks (Kyleena, Skyla, Mirena) after delivery, or until the uterus is fully involuted
  • If involution is delayed, wait until involution is complete before insertion
  • If woman has not yet had a period, consider the possibility of ovulation and conception occurring before insertion
  • May be inserted any time the healthcare professional assesses the woman is not pregnant
  • If not inserted during the first 7 days of the menstrual cycle, use a barrier method of contraception or abstain from vaginal intercourse for 7 days after insertion to prevent pregnancy
  • Increased risk of perforation in lactating women
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Interactions

Interaction Checker

and levonorgestrel intrauterine

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    Interactions Found

    Contraindicated

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        Significant - Monitor Closely

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            Adverse Effects

            >10%

            Unscheduled uterine bleeding (31.9%)

            Decreased uterine bleeding (23.4%)

            Abdominal/pelvic pain (22.6%)

            Amenorrhea (18.4%)

            Headache/migraine (16.3%)

            Genital discharge (14.9%)

            Increased scheduled uterine bleeding (11.9%)

            Vulvovaginitis (10.5%)

            1-10%

            Breast pain (8.5%)

            Back pain (7.9%)

            Benign ovarian cyst and associated complications (7.5%)

            Acne (6.8%)

            Dysmenorrhea (6.4%)

            Depression/depressive mood (6.4%)

            Female genital tract bleeding (3.5%)

            <1%

            Angioedema

            Cervical perforation

            Failed insertion

            Sepsis

            Uterine bleeding

            Device breakage

            Pulmonary emboli

            Deep vein thrombosis and stroke

            Increased blood pressure

            Postmarketing Reports

            Arterial thrombotic and venous thromboembolic events, including cases of pulmonary emboli, deep vein thrombosis and stroke

            Device breakage

            Hypersensitivity (eg, rash, urticaria and angioedema)

            Increased blood pressure

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            Warnings

            Contraindications

            Pregnancy or suspicion of pregnancy; cannot be used for postcoital contraception (emergency contraception)

            Congenital or acquired uterine anomaly including fibroids if they distort the uterine cavity

            Acute pelvic inflammatory disease or a history of pelvic inflammatory disease unless there has been a subsequent intrauterine pregnancy

            Postpartum endometritis or infected abortion in the past 3 months

            Known or suspected uterine or cervical neoplasia

            Known or suspected breast cancer or other progestin-sensitive cancer, now or in the past

            Uterine bleeding of unknown etiology

            Untreated acute cervicitis or vaginitis, including bacterial vaginosis or other lower genital tract infections until infection is controlled

            Acute liver disease or liver tumor (benign or malignant)

            Conditions associated with increased susceptibility to pelvic infections

            Previously inserted intrauterine device (IUD) that has not been removed

            Hypersensitivity to any component of this product

            Cautions

            Pregnant women whose device cannot be removed or if patient chooses not to have it removed, increases risk of miscarriage, sepsis, premature labor and premature delivery; advise patient of isolated reports of virilization of the female fetus following local exposure to drug during pregnancy with an IUS in place

            Evaluate women for ectopic pregnancy; ~50% of pregnancies that occur with IUD are likely to be ectopic; also consider possibility of ectopic pregnancy in case of lower abdominal pain, especially in association with missed menses or if an amenorrheic woman starts bleeding

            Severe infection, including group A streptococcal sepsis reported

            Bleeding pattern alterations may occur, including amenorrhea, infrequent bleeding, prolonged bleeding, or irregular bleeding

            Perforation may occur, most often during insertion; an interim analysis from a large postmarketing safety study shows an increased risk of perforation in lactating women; perforation risk may be increased in women with fixed retroverted uteri, and during the postpartum period; perforation may also occur at any time during IUS use; perforation may reduce contraceptive efficacy and result in pregnancy; this may be associated with severe pain and continued bleeding

            Inform women who use product about recognizing signs and symptoms of ectopic pregnancy and promptly reporting them to their healthcare professional, and about the associated risks of ectopic pregnancy (eg, loss of fertility)

            Exclude underlying endometrial pathology (eg, polyps or cancer) prior to insertion of device in women with persistent or uncharacteristic bleeding; irregular bleeding/spotting is common during first months of use and may preclude adequate assessment after insertion

            If the threads are not visible or are significantly shortened, they may have broken or retracted into cervical canal or uterus; consider possibility that IUS may have been displaced, (for example, expulsed or perforated the uterus); exclude pregnancy and verify location of device by an appropriate diagnostic method

            Women who currently have or have had breast cancer, or have a suspicion of breast cancer, should not use hormonal contraception, because some breast cancers are hormone-sensitive

            Product not intended for use in menopausal women

            Women with symptomatic actinomycosis should have device removed and should receive antibiotics

            Ovarian cysts may occur

            Assess whether woman is at increased risk of infection (eg, leukemia, acquired immune deficiency syndrome [AIDS], IV drug abuse), or has history of PID unless there has been a subsequent intrauterine pregnancy; device does not protect against HIV/STI transmission

            Pelvic infection

            • PID may be asymptomatic but still result in tubal damage and its sequelae
            • Promptly examine users with complaints of lower abdominal or pelvic pain, odorous discharge, unexplained bleeding, fever, genital lesions or sores; remove device in cases of recurrent endometritis or PID, or if an acute pelvic infection is severe or does not respond to treatment
            • IUDs have been associated with an increased risk of PID, most likely due to organisms being introduced into the uterus during insertion
            • PID is often associated with a sexually transmitted infection (STI), and Mirena does not protect against STI; risk of PID is greater for women who have multiple sexual partners, and also for women whose sexual partner(s) have multiple sexual partners
            • Women who have had PID are at increased risk for a recurrence or re-infection; in particular, ascertain whether woman is at increased risk of infection (for example, leukemia, acquired immune deficiency syndrome [AIDS], intravenous drug abuse)
            • Following a diagnosis of PID, or suspected PID, obtain bacteriologic specimens and initiate antibiotic therapy promptly; removal of device after initiation of antibiotic therapy is usually appropriate

            Perforation

            • Perforation may occur, most often during insertion; an interim analysis from a large postmarketing safety study shows an increased risk of perforation in lactating women
            • Risk of uterine perforation is increased in women who have recently given birth, and in women who are breastfeeding at time of insertion and during postpartum period; risk of perforation may be increased if device is inserted when the uterus is fixed, retroverted or not completely involuted
            • Perforation may also occur at any time during IUS use and may reduce contraceptive efficacy and result in pregnancy; this may be associated with severe pain and continued bleeding
            • If perforation occurs, locate, and remove device; surgery may be required; delayed detection or removal of device in case of perforation may result in migration outside uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses and erosion of adjacent viscera

            Bleeding pattern alterations

            • Device can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea; during first 3–6 months of use, number of bleeding and spotting days may be higher and bleeding patterns may be irregular
            • Thereafter number of bleeding and spotting days usually decreases but bleeding may remain irregular; if bleeding irregularities develop during prolonged treatment, take appropriate diagnostic measures to rule out endometrial pathology
            • Amenorrhea develops in approximately 20% of device users by one year
            • Consider possibility of pregnancy if menstruation does not occur within six weeks of onset of previous menstruation; once pregnancy has been excluded, repeated pregnancy tests are generally not necessary in amenorrheic women unless indicated, for example, by other signs of pregnancy or by pelvic pain
            • In most women with heavy menstrual bleeding, the number of bleeding and spotting days may also increase during initial months of therapy but usually decrease with continued use; the volume of blood loss per cycle progressively becomes reduced

            Expulsion

            • Partial or complete expulsion of intrauterine device may occur resulting in loss of contraceptive protection; expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed
            • Drug typically decreases menstrual bleeding over time; an increase of menstrual bleeding may be indicative of an expulsion
            • Consider further diagnostic imaging, such as x-ray, if expulsion is suspected based on ultrasound
            • Risk of expulsion is increased with insertions immediately after delivery and appears to be increased with insertion after second-trimester abortion based on limited data; in a large postmarketing safety study conducted in US, risk of expulsion was lower with breastfeeding status
            • Remove a partially expelled device; if expulsion has occurred, a new device can be inserted any time the provider can be reasonably certain the woman is not pregnant
            • A 5-year expulsion rate of 3.5% (59 out of 1,690 subjects) reported in clinical trials; delay insertion a minimum of 4 weeks or until uterine involution complete following a delivery or a second-trimester abortion

            MRI

            • Safe scanning with MRI may occur under specific conditions
            • static magnetic field ≤3 Tesla
            • spatial gradient field ≤36,000 Gauss/cm (T/m)
            • maximum SAR (whole body) of 4W/kg in first level controlled mode for 15 min

            Clinical Considerations for Use and Removal

            • Coagulopathy or use of anticoagulants
            • Migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia
            • Exceptionally severe headache
            • Marked increase of blood pressure
            • Severe arterial disease such as stroke or myocardial infarction
            • Consider removing device if jaundice or uterine or cervical malignancy occur during use

            Drug interaction overview

            • Drug interactions not studied; drugs or herbal products that induce or inhibit drug metabolizing enzymes, including CYP3A4, may decrease or increase, respectively, the serum concentrations of drug during use; however, contraceptive effect of drug is mediated via direct release of drug into uterine cavity and is unlikely to be affected by drug interactions via enzyme induction or inhibition
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            Pregnancy & Lactation

            Pregnancy

            Contraindicated in pregnancy or suspected pregnancy

            If a females becomes pregnant with IUD in place, risk of ectopic pregnancy is increased as well as miscarriage, sepsis, premature labor, and premature delivery

            Isolated cases of virilization of external genitalia of female fetus following exposure to levonorgestrel during pregnancy with a levonorgestrel intrauterine device in place

            Remove IUD, if possible, if pregnancy occurs in a woman using IUD

            If a woman becomes pregnant with levonorgestrel intrauterine device in place and the woman chooses not to have it removed or can’t be removed, advise her of reports of virilization of the female fetus following local exposure to levonorgestrel during pregnancy; closely follow pregnancy

            Female and male reproductive potential

            • Probability to conceive within 12 months after removal of intrauterine system reported to be approximately 77%

            Lactation

            Published studies report presence of LNG in human milk

            Small amounts of progestins (~0.1% of the total maternal doses) were detected in the breast milk of nursing mothers who used other LNG-releasing IUSs, resulting in exposure of LNG to the breastfed infants

            There are no reports of adverse effects in breastfed infants with maternal use of progestin-only contraceptives

            Isolated cases of decreased milk production have been reported with a LNG-releasing IUS

            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

            Local mechanism by which continuously released LNG enhances contraceptive effectiveness has not been demonstrated

            Suggested mechanisms of preventing pregnancy are thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, and alteration of the endometrium

            Absorption

            LNG concentrations

            • Kyleena
              • 12 months: 199 pg/mL
              • 24 months: 120 pg/mL
              • 36 months: 122 pg/mL
              • 48 months: 79 pg/mL
              • 60 months: 65 pg/mL
            • Liletta
              • 6 months: 195 pg/mL
              • 12 months: 168 pg/mL
              • 24 months: 150 pg/mL
              • 36 months: 132 pg/mL
              • 48 months: 114 pg/mL
              • 60 months: 101 pg/mL
              • 72 months: 93 pg/mL
            • Mirena
              • 12 months: 150 pg/mL
              • 24 months: 192 pg/mL
              • 60 months: 159 pg/mL
              • 72 months: 121 pg/mL
            • Skyla
              • 12 months: 7 pg/mL
              • 24 months: 62 pg/mL
              • 36 months: 72 pg/mL

            Distribution

            Vd: ~1.8 L//kg

            Protein-bound

            • Mirena: ~97.5-99%
            • Liletta: ~98.9%

            Metabolism

            LNG conjugates to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in serum

            Also, studies demonstrated oxidative metabolism of LNG catalyzed by CYP enzymes, especially CYP3A4

            Elimination

            Clearance

            • Skyla and Kyleena: 1 mL/min/kg

            Half-life

            • Mirena: ~17 hr
            • Skyla: ~ 20 hr
            • Liletta: ~13.9 hr
            • Kyleena: ~20 hr

            Excretion

            • All formulations: ~45% (urine); ~32% (feces)
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            Administration

            Intrauterine Administration

            See prescribing information for full instructions

            Ensure use of aseptic technique throughout the entire procedure

            Open package; do NOT move the slider downward at this time as this may prematurely release the threads of the device

            Once the slider is moved below the mark, device cannot be reloaded

            Set the flange

            Device is ready to be inserted ~1.5–2 cm from the cervix

            Do not force inserter; if necessary, dilate cervical canal

            Advance to fundal position; release insertion

            Storage

            All formulations

            • Protect from light
            • Store at 25ºC (77ºF); excursions permitted to 15–30ºC (59–86ºF)
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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.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
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