Levonorgestrel

Pronunciation

Pronunciation: LEE-voe-nor-JES-trel
Class: Contraceptive hormone, Emergency contraceptive

Trade Names

Mirena
- Intrauterine system 52 mg (releases approximately 20 mcg/day)

Next Choice
- Tablets, oral 0.75 mg

Plan B
- Tablets, oral 0.75 mg

Plan B One-Step
- Tablets, oral 1.5 mg

Pharmacology

Levonorgestrel, as contraception, is a progestogen that causes thickening of cervical mucus, inhibition of sperm capacitation or survival, and alteration of the endometrium. Levonorgestrel, as an emergency contraceptive, prevents ovulation or fertilization by altering tubal transport of sperm and/or ova, as well as inhibiting implantation by altering the endometrium.

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Pharmacokinetics

Absorption

Plasma levels are approximately 150 to 200 pg/mL after the first few weeks, and 180, 192, and 159 pg/mL after 12, 24, and 60 mo of use, respectively (intrauterine). Rapidly and completely absorbed after oral administration. Bioavailability is approximately 100% (oral). C max and T max are approximately 14.1 ng/mL and 1.6 h, respectively, for Plan B , and 19.1 ng/mL and 1.7 h, respectively, for Next Choice and Plan B One-Step .

Distribution

Plasma levels with the levonorgestrel-releasing intrauterine system do not display peaks and troughs. Approximately 50% is bound to albumin and 47.5% is bound to sex hormone–binding globulin (oral); approximately 97.5% to 99% protein bound, principally to globulin and, to a lesser extent, to serum albumin (intrauterine). Vd is approximately 1.8 L/kg.

Metabolism

Extensively metabolized to a large number of inactive metabolites.

Elimination

The half-life is 17 h (after daily oral doses), 24 h ( Next Choice and Plan B ), and 28 h ( Plan B One-Step ). Both the parent drug and its metabolites are primarily excreted in the urine. Approximately 45% is excreted in the urine and 32% in feces, mostly as glucuronide conjugates.

Special Populations

Renal Function Impairment

No formal studies were conducted.

Hepatic Function Impairment

No formal studies were conducted.

Elderly

Not studied in women older than 65 y of age.

Race

There was a higher increase in the rate of pregnancy in Chinese women using Next Choice or Plan B One-Step ; the reason for this apparent increase is unknown. No studies have been conducted with Mirena .

Indications and Usage

Prevention of pregnancy, treatment of heavy menstrual bleeding for women who choose to use intrauterine contraception (intrauterine); emergency contraceptive (oral).

Contraindications

Oral

Known or suspected pregnancy; hypersensitivity.

Intrauterine device

Pregnancy or suspicion of pregnancy; congenital or acquired uterine anomaly, including fibroids if they distort the uterine cavity; acute pelvic inflammatory disease (PID) or history of PID unless there has been a subsequent intrauterine pregnancy; postpartum endometritis or infected abortion in past 3 mo; known or suspected uterine or cervical neoplasia or unresolved, abnormal Papanicolaou test; genital bleeding of unknown etiology; untreated acute cervicitis or vaginitis, including bacterial vaginosis or other lower genital tract infection, until the infection is controlled; acute liver disease or liver tumor (benign or malignant); conditions associated with increased susceptibility to pelvic infections; previously inserted intrauterine device that has not been removed; hypersensitivity to any component of this product; known or suspected carcinoma of the breast.

Dosage and Administration

Intrauterine device
Adults

Insert into uterine cavity within 7 days of onset of menstruation or immediately after first-trimester abortion. Replace every 5 y.

Discontinuation of therapy

If the patient has regular cycles, remove the intrauterine system during the first 7 days of the menstrual cycle and start the new birth control method.

If the patient has irregular cycles or amenorrhea, or if the intrauterine system is removed after the seventh day of the menstrual cycle, start the new method of birth control at least 7 days before removal of the intrauterine system.

Next Choice and Plan B
Emergency Contraception Adults and Children who have undergone menarche

PO 1 tablet (0.75 mg) as soon as possible within 72 h after unprotected intercourse; second tablet (0.75 mg) 12 h after the first dose.

Plan B One-Step
Emergency Contraception Adults and Children who have undergone menarche

PO 1 tablet (1.5 mg) as soon as possible within 72 h after unprotected intercourse or known or suspected contraceptive failure.

General Advice

  • The intrauterine system can be replaced by a new system at any time during the menstrual cycle.
  • If the intrauterine system is removed midcycle and the patient has had intercourse within the preceding week, she is at risk of pregnancy unless a new system is inserted immediately following removal.
  • Levonorgestrel oral emergency contraceptive can be used at any time during the menstrual cycle.
  • If the patient vomits within 1 h of taking Plan B or 2 h of taking Next Choice or Plan B One-Step , she should contact her health care provider to determine whether a repeat dose is required.

Storage/Stability

Intrauterine system and Plan B

Store between 59° and 86°F. Insert Mirena before the end of the month shown on the label.

Next Choice and Plan B One-Step

Store between 68° and 77°F.

Drug Interactions

Aprepitant, modafinil

Plasma concentrations and pharmacologic effects of levonorgestrel may be decreased. Instruct patients to use alternative or additional nonhormonal methods of contraception during aprepitant or modafinil therapy and for 1 mo following the last aprepitant or modafinil dose.

Azole antifungal agents (eg, fluconazole, ketoconazole)

Hormonal contraceptive failure and pregnancy may occur. Monitor the clinical response. Instruct patients to use alternative or additional nonhormonal methods of contraception.

Cyclosporine

Cyclosporine concentrations may be elevated, increasing the risk of toxicity. Monitor cyclosporine concentrations, as well as hepatic and renal function. Adjust the cyclosporine dose as needed.

Drugs that increase levonorgestrel metabolism (eg, barbiturates [eg, phenobarbital], bosentan, carbamazepine, felbamate, griseofulvin, hydantoins [eg, phenytoin], oxcarbazepine, rufinamide, thiazolidinediones [eg, pioglitazone])

Plasma concentrations and pharmacologic effects of levonorgestrel may be decreased. Monitor the clinical response. Instruct patients to use alternative or additional nonhormonal methods of contraception during coadministration.

Lamotrigine

Lamotrigine concentrations may be reduced, decreasing efficacy. Monitor the clinical response and adjust the lamotrigine dose as needed.

Protease inhibitors/non-nucleoside reverse transcriptase inhibitors

Increase or decrease in the plasma levels of progestin has been noted. Monitor the clinical response. It would be prudent to instruct patients to use alternative or additional nonhormonal methods of contraception during coadministration of these agents.

Rifamycins (eg, rifampin), St. John's wort

Plasma concentrations and pharmacologic effects of levonorgestrel may be decreased. If coadministration cannot be avoided, instruct patients to use alternative or additional nonhormonal methods of contraception.

Topiramate

Plasma concentrations and pharmacologic effects of levonorgestrel may be decreased. An alternative or nonhormonal method of birth control is recommended when topiramate is used for epilepsy at doses greater than 200 mg/day.

Tranexamic acid

The risk of thrombotic events may be increased with coadministration.

Adverse Reactions

Cardiovascular

Hypertension (less than 5%); bradycardia, syncope.

CNS

Fatigue, headache (17%); dizziness (11%); migraine (8%); depressed or altered mood (6%); decreased libido, nervousness (less than 5%).

Dermatologic

Acne (7%); alopecia, skin disorders, including eczema, rash, urticaria (less than 5%); dermatitis; hirsutism; hypertrichosis; pain, itching, or infection near implant site; scalp hair loss.

GI

Nausea (23%); abdominal pain (18%); vomiting (6%); diarrhea (5%); abdominal distension (less than 5%); abdominal discomfort, change in appetite.

Genitourinary

Uterine/vaginal bleeding alterations (52%); heavier menstrual bleeding (31%); menstrual changes (26%); amenorrhea (24%); intermenstrual bleeding and spotting (23%); lighter menstrual bleeding, pelvic pain (13%); ovarian cysts (12%); breast tenderness (11%); menorrhagia (6%); breast pain, delay of menses, intrauterine device expulsion, vaginal discharge (5%); cervicitis/Papanicolaou smear normal/class II, dysmenorrhea, dyspareunia, vulvovaginitis (less than 5%); leukorrhea; oligomenorrhea; prolonged, irregular, frequent, or scanty bleeding; spotting; vaginitis (postmarketing).

Metabolic

Weight gain (less than 5%).

Respiratory

Sinusitis, upper respiratory tract infection.

Miscellaneous

Anemia, back pain, edema (less than 5%); adnexal enlargement, breast discharge, mastalgia, musculoskeletal pain; angioedema, device breakage (postmarketing).

Precautions

Warnings

Counsel patients that this product does not protect against HIV infection (AIDS) or other STDs.


Monitor

Reexamine and evaluate patients 4 to 12 wk after insertion of the intrauterine system and once yearly thereafter, or more frequently if clinically indicated. Examine users with complaints of fever, genital lesions, pain, odorous discharge, sores, or unexplained bleeding. Evaluate patients with lower abdominal pain with or without missed periods and patients who develop vaginal bleeding and were previously amenorrheic for the possibility of ectopic pregnancy. Monitor blood glucose concentrations in patients with diabetes. Closely monitor patients on long-term corticosteroids and diabetic patients on insulin for infection.


Pregnancy

Category X . Levonorgestrel is not effective in terminating an existing pregnancy.

Lactation

Excreted in breast milk.

Children

Use before menarche is not indicated.

Elderly

Not intended for use in postmenopausal women.

Fertility

About 80% of women wishing to become pregnant conceived within 12 mo after removal of the intrauterine system. A rapid return of fertility is likely following treatment with oral levonorgestrel.

Special Risk Patients

Use the intrauterine system with caution in patients who have a coagulopathy or are receiving anticoagulants; marked increase in BP; severe arterial disease, such as stroke or MI; a migraine, focal migraine with asymmetrical visual loss, or other symptoms indicating transient cerebral ischemia; or an exceptionally severe headache.

Bleeding irregularities

Most women can expect a variation in menstrual bleeding patterns, ranging from heavy bleeding to amenorrhea.

Breast cancer

Women who currently have or have had breast cancer should not use hormonal contraceptives. Spontaneous cases of breast cancer have been reported with the intrauterine system.

Contraception

Levonorgestrel (oral) is not recommended for routine use as a contraceptive.

Delayed follicular atresia

Follicle may grow beyond usual size and may resemble ovarian cyst.

Diabetes

May experience a slight deterioration in glucose tolerance, with increases in plasma insulin.

Ectopic pregnancies

Have occurred, although relationship to drug is not established.

Embedment

Embedment of the intrauterine system in the myometrium may occur, leading to decreased contraceptive effectiveness.

Expulsion

Partial or complete expulsion of the intrauterine system may occur.

Intrauterine pregnancy

Risk of septic abortion, miscarriage, premature delivery, premature labor, and sepsis may be increased with the intrauterine system. Remove intrauterine system if possible. Long-term effects on offspring are unknown.

Intrauterine system removal

Should occur for the following medical reasons: endometrial or cervical malignancy, endometriosis, intractable pelvic pain, menorrhagia and/or metrorrhagia producing anemia, pelvic infection, pregnancy, severe dyspareunia, STD, symptomatic genital actinomycosis, or uterine or cervical perforation. Consider removal if any of the following conditions arise for the first time: migraine or focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia, an exceptionally severe headache, jaundice, marked increase in BP, or severe arterial disease, such as stroke or MI.

Neurovascular episodes

Syncope, bradycardia, or other neurovascular episodes may occur during insertion of the intrauterine system.

Ovarian cysts

May occur.

PID

Use of intrauterine devices has been associated with an increased risk of PID.

Perforation

Perforation of the uterus and cervix by the intrauterine system may occur.

Postpartum

Intrauterine system should not be inserted until 6 wk postpartum or until involution of the uterus is complete to reduce the incidence of perforation and expulsion.

Sepsis

Cases of group A streptococcal sepsis have occurred rarely in patients following insertion of the intrauterine system.

STDs

Levonorgestrel does not protect against HIV (AIDS) or other STDs.

Valvular/Congenital heart disease

Patients with certain types of valvular or congenital heart disease and surgically constructed systemic-pulmonary shunts are at increased risk of infective endocarditis, and use of the intrauterine system may represent a potential source of septic emboli.

Overdosage

Symptoms

Fluid retention, nausea, uterine bleeding irregularities, vomiting.

Patient Information

  • Intrauterine
  • Advise patients that the intrauterine system is used to prevent pregnancy and does not protect against HIV (AIDS) or other STDs.
  • Explain to patients that the intrauterine system is a hormone-releasing system placed in the uterus to prevent pregnancy for up to 5 y. Inform patients that the intrauterine system should be removed after 5 y, but their health care provider can replace it with a new system at that time if they choose to continue using it.
  • Advise patients that they may become pregnant as soon as the system is removed.
  • Instruct patients to inform their health care provider if they recently had a baby, are breast-feeding, are diabetic, were born with heart disease or have problems with their heart valves, have problems with blood clotting, or take medicine to reduce clotting.
  • Instruct patients to contact their health care provider right away if they think they are pregnant. If they become pregnant while using the intrauterine system, they may have an ectopic pregnancy. Unusual vaginal bleeding or abdominal pain may be a sign of ectopic pregnancy.
  • Explain to patients that there are also risks if they become pregnant while using the intrauterine system and the pregnancy is in the uterus. Severe infection, miscarriage, premature delivery, and even death can occur with pregnancies that continue with an intrauterine device in place. If this occurs, it may be necessary to try to remove the intrauterine system, even though removing it may cause a miscarriage. If the system cannot be removed, advise patients to talk with their health care provider about the benefits and risks of continuing the pregnancy.
  • Inform patients that for the first 3 to 6 mo, their monthly period may become irregular. They may also have frequent spotting or light bleeding. A few women have heavy bleeding during this time. After their body adjusts, the number of bleeding days is likely to decrease, and their periods may stop altogether.
  • Inform patients that the system may come out by itself. This is called expulsion. They may become pregnant if the system comes out. Advise patients to use a backup birth control method, such as condoms, and to call their health care provider if they notice that the system has come out.
  • Advise patients to call their health care provider if they think they are pregnant; have pelvic pain or pain during sex; have unusual vaginal discharge or genital sores; have unexplained fever; might be exposed to STDs; cannot feel the system's threads; develop very severe or migraine headaches; have yellowing of the skin or whites of the eyes (these may be signs of liver problems); have a stroke or heart attack; have a partner who becomes HIV-positive; have severe or prolonged vaginal bleeding; or miss a menstrual period.
  • Emergency contraceptive
  • Instruct patients to take levonorgestrel emergency contraceptive as soon as possible and not more than 72 h after unprotected intercourse or known or suspected contraceptive failure.
  • Advise patients that if vomiting occurs within 1 h of taking Plan B or within 2 h of taking Next Choice or Plan B One-Step , they should immediately contact their health care provider to discuss whether to take another tablet.
  • Advise patient to seek medical attention if severe lower abdominal pain occurs 3 to 5 wk after taking levonorgestrel in order to rule out ectopic pregnancy, or if their period is delayed more than 1 wk beyond the expected date after taking emergency contraceptives.
  • Advise patients that for women 17 y of age and younger, Plan B is available only by prescription. For women younger than 17 y of age, Next Choice and Plan B One-Step are available only by prescription.

Copyright © 2009 Wolters Kluwer Health.

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