Levonorgestrel

Pronunciation

(LEE voe nor jes trel)

U.S. Brand Names

Mirena®; Plan B®

Synonyms

LNg 20

Generic Available

Canadian Brand Names

Mirena®; Norplant® Implant; Plan B™

Use

Prevention of pregnancy

Pregnancy Risk Factor

Pregnancy Implications

Epidemiologic studies have not shown an increased risk of birth defects when used prior to pregnancy or inadvertently during early pregnancy, although rare reports of congenital anomalies have been reported.

Intrauterine system: Women who become pregnant with an IUD in place risk septic abortion (septic shock and death may occur), removal of IUD may result in pregnancy loss. In addition, miscarriage, premature labor, and premature delivery may occur if pregnancy is continued with IUD in place.

Lactation

Enters breast milk/use caution (AAP rates "compatible")

Contraindications

Hypersensitivity to levonorgestrel or any component of the formulation; undiagnosed abnormal uterine bleeding, active hepatic disease or malignant tumors, active thrombophlebitis, or thromboembolic disorders (current or history of), known or suspected carcinoma of the breast; history of intracranial hypertension; renal impairment; pregnancy

Additional product-specific contraindications: Intrauterine system: Congenital or acquired uterine anomaly, acute pelvic inflammatory disease, history of pelvic inflammatory disease (unless there has been a subsequent intrauterine pregnancy), postpartum endometritis, infected abortion within past 3 months, known or suspected uterine or cervical neoplasia, unresolved/abnormal Pap smear, untreated acute cervicitis or vaginitis, patient or partner with multiple sexual partners, conditions which increase susceptibility to infections (ie, leukemia, AIDS, I.V. drug abuse), unremoved IUD, history of ectopic pregnancy, conditions which predispose to ectopic pregnancy

Warnings/Precautions

Menstrual bleeding patterns may be altered, missed menstrual periods should not be used to identify early pregnancy. These products do not protect against HIV infection or other sexually-transmitted diseases. Patients presenting with lower abdominal pain should be evaluated for follicular atresia and ectopic pregnancy. Patients receiving enzyme-inducing medications should be evaluated for an alternative method of contraception. Levonorgestrel may affect glucose tolerance, monitor serum glucose in patients with diabetes. Safety and efficacy for use in renal or hepatic impairment have not been established. Use with caution in conditions that may be aggravated by fluid retention, depression, or history of migraine. Only for use in women of reproductive age.

Use of combination hormonal contraceptives increases the risk of cardiovascular side effects in women who smoke cigarettes, especially those who are >35 years of age; although this may be an estrogen-related effect, the risk with progestin-only contraceptives is not known and women should be strongly advised not to smoke. Combination hormonal contraceptives may lead to increased risk of myocardial infarction and should be used with caution in patients with risk factors for coronary artery disease; the actual risk with progestin-only contraceptives is not known, however, there have been postmarketing reports of myocardial infarction in women using levonorgestrel-only contraception. May increase the risk of thromboembolism; discontinue therapy if this occurs. Combination hormonal contraceptives may have a dose-related risk of vascular disease and hypertension; strokes have also been reported with postmarketing use of levonorgestrel-only contraception. Women with hypertension should be encouraged to use a nonhormonal form of contraception. The use of combination hormonal contraceptives has been associated with a slight increase in frequency of breast cancer (studies are not consistent); studies with progestin only contraceptives have been similar. Retinal thrombosis has been reported (rarely) with combination hormonal contraceptives and may be related to the estrogen component, however, progestin-only therapy should also be discontinued with unexplained partial or complete loss of vision.

Additional formulation-specific warnings:

Intrauterine system: Increased incidence of group A streptococcal sepsis and pelvic inflammatory disease (may be asymptomatic); may perforate uterus or cervix; risk of perforation is increased in lactating women; partial penetration or embedment in the myometrium may decrease effectiveness and lead to difficult removal; postpartum insertion should be delayed until uterine involution is complete; use caution in patients with coagulopathy or receiving anticoagulants

Oral tablet: Not intended to be used for routine contraception and will not terminate an existing pregnancy

Adverse Reactions

Intrauterine system:

>5%:

Cardiovascular: Hypertension

Central nervous system: Headache, depression, nervousness

Dermatologic: Acne

Endocrine & metabolic: Breast pain, dysmenorrhea, decreased libido, abnormal Pap smear, amenorrhea (20% at 1 year), enlarged follicles (12%)

Gastrointestinal: Abdominal pain, nausea, weight gain

Genitourinary: Leukorrhea, vaginitis

Neuromuscular & skeletal: Back pain

Respiratory: Upper respiratory tract infection, sinusitis

<3% and postmarketing reports: Alopecia, anemia, cervicitis, dyspareunia, eczema, failed insertion, migraine, sepsis, vomiting

Oral tablets:

>10%:

Central nervous system: Fatigue (17%), headache (17%), dizziness (11%)

Endocrine & metabolic: Heavier menstrual bleeding (14%), lighter menstrual bleeding (12%), breast tenderness (11%)

Gastrointestinal: Nausea (23%), abdominal pain (18%)

1% to 10%: Gastrointestinal: Vomiting (6%), diarrhea (5%)

Overdosage/Toxicology

Can result if >6 capsules are in situ . Symptoms include uterine bleeding irregularities and fluid retention.

Drug Interactions

Substrate of CYP3A4 (major)

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of levonorgestrel. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: St John's wort (an enzyme inducer) may decrease serum levels of levonorgestrel.

Stability

Store at room temperature of 25°C (77°F).

Mechanism of Action

Pregnancy may be prevented through several mechanisms: Thickening of cervical mucus, which inhibits sperm passage through the uterus and sperm survival; inhibition of ovulation, from a negative feedback mechanism on the hypothalamus, leading to reduced secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH); inhibition of implantation. Levonorgestrel is not effective once the implantation process has begun.

Pharmacodynamics/Kinetics

Duration: Intrauterine system: Up to 5 years

Absorption: Rapid and complete

Protein binding: Highly bound to albumin and sex hormone-binding globulin

Metabolism: To inactive metabolites

Bioavailability: 100%

Half-life elimination: Oral tablet: ~24 hours

Excretion: Primarily urine

Dosage

Adults: Females:

Long-term prevention of pregnancy: Intrauterine system: To be inserted into uterine cavity; should be inserted within 7 days of onset of menstruation or immediately after 1st trimester abortion; releases 20 mcg levonorgestrel/day over 5 years. May be removed and replaced with a new unit at anytime during menstrual cycle; do not leave any one system in place for >5 years

Emergency contraception: Oral tablet: One 0.75 mg tablet as soon as possible within 72 hours of unprotected sexual intercourse; a second 0.75 mg tablet should be taken 12 hours after the first dose; may be used at any time during menstrual cycle

Dosage adjustment in renal impairment: Safety and efficacy have not been established

Dosage adjustment in hepatic impairment: Safety and efficacy have not been established

Elderly: Not intended for use in postmenopausal women

Administration

Intrauterine system: Inserted in the uterine cavity, to a depth of 6-9 cm, with the provided insertion device; should not be forced into the uterus

Monitoring Parameters

Monitor for prolonged menstrual bleeding, amenorrhea, irregularity of menses, Pap smear, blood pressure, serum glucose in patients with diabetes, LDL levels in patients with hyperlipidemias

Reference Range

Contraceptive protection usually with plasma levonorgestrel concentrations of 0.29-0.35 ng/mL. Due to variability in individual responses, blood levels alone are not predictive of pregnancy risk.

Test Interactions

Decreased concentrations of sex hormone-binding globulin; decreased thyroxine concentrations (slight); increased triiodothyronine uptake

Patient Education

This drug does not protect against HIV infection or other sexually-transmitted diseases. Cigarette smoking is not recommended. You may experience cramping, headache, abdominal discomfort, hair loss, weight changes, or unusual menses (breakthrough bleeding, irregularity, excessive bleeding). Report sudden acute headache or visual disturbance, unusual nausea or vomiting, any loss of feeling in arms or legs, or lower abdominal pain. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Consult prescriber if breast-feeding.

Intrauterine system: This method provides up to 5 years of birth control from a T-shaped device inserted into the uterus. It will be inserted and removed by your prescriber. Notify your prescriber if the system comes out by itself, if you have long-lasting or heavy bleeding, unusual vaginal discharge, low abdominal pain, painful sexual intercourse, chills or fever. There is an increased risk of ectopic pregnancy with this product. Thread placement should be checked following each menstrual cycle; do not pull thread.

Tablet: This method provides emergency contraception. It is used after your normal form of birth control has failed, or following unprotected sexual intercourse. It should be used within 72 hours. Contact prescriber if you vomit within 1 hour of taking either dose.

Nursing Implications

Caution patient about need for annual medical exams.

Additional Information

Intrauterine system: The cumulative 5-year pregnancy rate is ~0.7 pregnancies/100 users. Over 70% of women in the trials had previously used IUDs. The reported pregnancy rate after 12 months was

0.2 pregnancies/100 users. Approximately 80% of women who wish to conceive have become pregnant within 12 months of device removal. The recommended patient profile for this product: A woman who has at least one child, is in a stable and mutually-monogamous relationship, no history of pelvic inflammatory disease, and no history of ectopic pregnancy or predisposition to ectopic pregnancy.

Oral tablet: When used as directed for emergency contraception, the expected pregnancy rate is decreased from 8% to 1%. Approximately 87% of women have their next menstrual period at approximately the expected time. A rapid return to fertility following use is expected.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause nervousness or dizziness

Mental Health: Effects on Psychiatric Treatment

Carbamazepine may decrease the effects of levonorgestrel

Dosage Forms

Intrauterine device (Mirena®): 52 mg levonorgestrel/unit [releases levonorgestrel 20 mcg/day]

Tablet (Plan B®): 0.75 mg

References

Fotherby K, "Levonorgestrol. Clinical Pharmacokinetics," Clin Pharmacokinet , 1995, 28(3):203-15.

Frank ML and DiMaria C, "Levonorgestrel Subdermal Implants," Drug Saf , 1997, 17(6):360-8.

Frost O, "Tracheo-Oesophageal Fistula Associated With Hormonal Contraception During Pregnancy," Br Med J , 1976, 2:978.

Viegas OA, Koh SC, and Ratnam SS, "The Effects of Reformulated 2-Rod Norplant® Implant on Hemostasis After Three Years," Contraception , 1996, 54(4):219-28.

Wysowski DK and Green L, "Serious Adverse Events in Norplant® Users Reported to the Food and Drug Administration's MedWatch Spontaneous Reporting System," Obstet Gynecol , 1995, 85(4):538-42.

International Brand Names

duofem® (DE); Ecee2® (IN); Follistrel® (SE); Imediat N® (AR); Jadelle® (FI); Jadena® (ID); Levogynon® (DE); Levonelle® (GB, IE, IT, NZ, PT); Levonorgestrel L.CH.® (CL); Levonova® (DK, NO, SE); Madonna® (TH); Microlut® (AR, AU, BE, CH, CL, CO, DE, LU, MX, NZ, RU); Microluton® (DK, FI, NO); Microval® (AU, BE, CL, CO, FR, GB, LU, NZ, RO, ZA); Mikro-30 Wyeth® (DE); 28 mini® (DE); Mirena® (AT, AU, BE, BG, CA, CH, CO, CR, CZ, DE, DO, ES, FI, FR, GB, GT, HN, HR, HU, IE, IL, IT, LU, NL, NZ, PA, PT, RO, RU, SG, SI, SV, TR, YU, ZA); Norgeston® (GB); Norgestrel Max® (AR); Norlevo® (BE, CH, DK, ES, FI, FR, IT, NO, PT, SE, SI, ZA); Norplant® (CZ, GB, ID, LU, RO, RU, SE, TH); Norplant® Implant (CA); Nortrel® (BR); Plan B™ (CA); Postinor-2® (BR, CZ, IL, NZ, RO, SG, TH); Postinor® (AT, BD, CH, CZ, DK, EG, ES, HU, PL, RO, RU, SE, SY, YU); Rigesoft® (HU); Vikela® (AT)

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