Included as part of the PRECAUTIONS section.

Ectopic Pregnancy

Evaluate women who become pregnant while using Mirena (levonorgestrel-releasing intrauterine system) for ectopic pregnancy. Up to half of pregnancies that occur with Mirena (levonorgestrel-releasing intrauterine system) in place are ectopic. The incidence of ectopic pregnancy in clinical trials that excluded women with risk factors for ectopic pregnancy was approximately 0.1% per year.

Tell women who choose Mirena (levonorgestrel-releasing intrauterine system) about the risks of ectopic pregnancy, including the loss of fertility. Teach them to recognize and report to their physician promptly any symptoms of ectopic pregnancy. Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection carry a higher risk of ectopic pregnancy.

The risk of ectopic pregnancy in women who have a history of ectopic pregnancy and use Mirena (levonorgestrel-releasing intrauterine system) is unknown. Clinical trials of Mirena (levonorgestrel-releasing intrauterine system) excluded women with a history of ectopic pregnancy.

Intrauterine Pregnancy

If pregnancy should occur with Mirena (levonorgestrel-releasing intrauterine system) in place, Mirena (levonorgestrel-releasing intrauterine system) should be removed. Removal or manipulation of Mirena (levonorgestrel-releasing intrauterine system) may result in pregnancy loss. In the event of an intrauterine pregnancy with Mirena (levonorgestrel-releasing intrauterine system) , consider the following:

Septic abortion

In patients becoming pregnant with an IUD in place, septic abortion—with septicemia, septic shock, and death—may occur.

Continuation of pregnancy

If a woman becomes pregnant with Mirena (levonorgestrel-releasing intrauterine system) in place and if Mirena (levonorgestrel-releasing intrauterine system) cannot be removed or the woman chooses not to have it removed, she should be warned that failure to remove Mirena (levonorgestrel-releasing intrauterine system) increases the risk of miscarriage, sepsis, premature labor and premature delivery. She should be followed closely and advised to report immediately any flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge or leakage of fluid.

Long-term effects and congenital anomalies

When pregnancy continues with Mirena (levonorgestrel-releasing intrauterine system) in place, long-term effects on the offspring are unknown. As of September 2006, 390 live births out of an estimated 9.9 million Mirena (levonorgestrel-releasing intrauterine system) users had been reported. Congenital anomalies in live births have occurred infrequently. No clear trend towards specific anomalies has been observed. Because of the intrauterine administration of levonorgestrel and local exposure of the fetus to the hormone, the possibility of teratogenicity following exposure to Mirena (levonorgestrel-releasing intrauterine system) cannot be completely excluded. Some observational data support a small increased risk of masculinization of the external genitalia of the female fetus following exposure to progestins at doses greater than those currently used for oral contraception. Whether these data apply to Mirena (levonorgestrel-releasing intrauterine system) is unknown.

Sepsis

As of September 2006, 9 cases of Group A streptococcal sepsis (GAS) out of an estimated 9.9 million Mirena (levonorgestrel-releasing intrauterine system) users had been reported. In some cases, severe pain occurred within hours of insertion followed by sepsis within days. Because death from GAS is more likely if treatment is delayed, it is important to be aware of these rare but serious infections. Aseptic technique during insertion of Mirena (levonorgestrel-releasing intrauterine system) is essential. GAS sepsis may also occur postpartum, after surgery, and from wounds.

Pelvic Inflammatory Disease (PID)

Mirena (levonorgestrel-releasing intrauterine system) is contraindicated in the presence of known or suspected PID or in women with a history of PID unless there has been a subsequent intrauterine pregnancy. Use of IUDs has been associated with an increased risk of PID. The highest risk of PID occurs shortly after insertion (usually within the first 20 days thereafter) [see WARNINGS AND PRECAUTIONS]. A decision to use Mirena (levonorgestrel-releasing intrauterine system) must include consideration of the risks of PID.

Women at increased risk for PID

PID is often associated with a sexually transmitted disease, and Mirena (levonorgestrel-releasing intrauterine system) does not protect against sexually transmitted disease. The 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.

PID warning to Mirena (levonorgestrel-releasing intrauterine system) users

All women who choose Mirena (levonorgestrel-releasing intrauterine system) must be informed prior to insertion about the possibility of PID and that PID can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Patients must be taught to recognize and report to their physician promptly any symptoms of pelvic inflammatory disease. These symptoms include development of menstrual disorders (prolonged or heavy bleeding), unusual vaginal discharge, abdominal or pelvic pain or tenderness, dyspareunia, chills, and fever.

Asymptomatic PID

PID may be asymptomatic but still result in tubal damage and its sequelae.

Treatment of PID

Following a diagnosis of PID, or suspected PID, bacteriologic specimens should be obtained and antibiotic therapy should be initiated promptly. Removal of Mirena (levonorgestrel-releasing intrauterine system) after initiation of antibiotic therapy is usually appropriate. Guidelines for PID treatment are available from the Centers for Disease Control (CDC), Atlanta, Georgia.

Actinomycosis has been associated with IUDs. Symptomatic women with IUDs should have the IUD removed and should receive antibiotics. However, the management of the asymptomatic carrier is controversial because actinomycetes can be found normally in the genital tract cultures in healthy women without IUDs. False positive findings of actinomycosis on Pap smears can be a problem. When possible, confirm the Pap smear diagnosis with cultures.

Irregular Bleeding and Amenorrhea

Mirena (levonorgestrel-releasing intrauterine system) can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea. During the first three to six months of Mirena (levonorgestrel-releasing intrauterine system) use, the number of bleeding and spotting days may be increased and bleeding patterns may be irregular. Thereafter the number of bleeding and spotting days usually decreases but bleeding may remain irregular. If bleeding irregularities develop during prolonged treatment, appropriate diagnostic measures should be taken to rule out endometrial pathology.

Amenorrhea develops in approximately 20% of Mirena (levonorgestrel-releasing intrauterine system) users by one year. The possibility of pregnancy should be considered if menstruation does not occur within six weeks of the 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 [see Clinical Studies].

In most women with heavy menstrual bleeding, the number of bleeding and spotting days may also increase during the initial months of therapy but usually decrease with continued use; the volume of blood loss per cycle progressively becomes reduced [see Clinical Studies].

Embedment

Embedment of Mirena (levonorgestrel-releasing intrauterine system) in the myometrium may occur. Embedment may decrease contraceptive effectiveness and result in pregnancy [see WARNINGS AND PRECAUTIONS]. An embedded Mirena (levonorgestrel-releasing intrauterine system) should be removed. Embedment can result in difficult removal and, in some cases surgical removal may be necessary.

Perforation

Perforation or penetration of the uterine wall or cervix may occur during insertion although the perforation may not be detected until some time later. If perforation occurs, pregnancy may result [see WARNINGS AND PRECAUTIONS]. Mirena (levonorgestrel-releasing intrauterine system) must be located and removed; surgery may be required. Delayed detection of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses and erosion of adjacent viscera.

The risk of perforation may be increased in lactating women, in women with fixed retroverted uteri, and during the postpartum period. To decrease the risk of perforation postpartum, Mirena (levonorgestrel-releasing intrauterine system) insertion should be delayed a minimum of 6 weeks after delivery or until uterine involution is complete. If involution is substantially delayed, consider waiting until 12 weeks postpartum. Inserting Mirena (levonorgestrel-releasing intrauterine system) immediately after first trimester abortion is not known to increase the risk of perforation, but insertion after second trimester abortion should be delayed until uterine involution is complete.

Expulsion

Partial or complete expulsion of Mirena (levonorgestrel-releasing intrauterine system) may occur [see WARNINGS AND PRECAUTIONS].

Symptoms of the partial or complete expulsion of any lUD may include bleeding or pain. However, the system can be expelled from the uterine cavity without the woman noticing it, resulting in the loss of contraceptive protection. Partial expulsion may decrease the effectiveness of Mirena (levonorgestrel-releasing intrauterine system) . As menstrual flow typically decreases after the first 3 to 6 months of Mirena (levonorgestrel-releasing intrauterine system) use, an increase of menstrual flow may be indicative of an expulsion. If expulsion has occurred, Mirena (levonorgestrel-releasing intrauterine system) may be replaced within 7 days of a menstrual period after pregnancy has been ruled out.

Ovarian Cysts

Since the contraceptive effect of Mirena (levonorgestrel-releasing intrauterine system) is mainly due to its local effect, ovulatory cycles with follicular rupture usually occur in women of fertile age using Mirena (levonorgestrel-releasing intrauterine system) . Sometimes atresia of the follicle is delayed and the follicle may continue to grow. Enlarged follicles have been diagnosed in about 12% of the subjects using Mirena (levonorgestrel-releasing intrauterine system) . Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases the enlarged follicles disappear spontaneously during two to three months observation. Persistent enlarged follicles should be evaluated. Surgical intervention is not usually required.

Breast Cancer

Women who currently have or have had breast cancer, or have a suspicion of breast cancer, should not use hormonal contraception because breast cancer is a hormone-sensitive tumor.

Spontaneous reports of breast cancer have been received during postmarketing experience with Mirena (levonorgestrel-releasing intrauterine system) . Because spontaneous reports are voluntary and from a population of uncertain size, it is not possible to use postmarketing data to reliably estimate the frequency or establish causal relationship to drug exposure. Two observational studies have not provided evidence of an increased risk of breast cancer during the use of Mirena (levonorgestrel-releasing intrauterine system) .

Patient Evaluation and Clinical Considerations

• A complete medical and social history, including that of the partner, should be obtained to determine conditions that might influence the selection of an IUD for contraception [see CONTRAINDICATIONS].
• Special attention must be given to ascertaining whether the woman is at increased risk of infection (for example, leukemia, acquired immune deficiency syndrome (AIDS), I.V. drug abuse), or has a history of PID unless there has been a subsequent intrauterine pregnancy. Mirena (levonorgestrel-releasing intrauterine system) is contraindicated in these women.
• A physical examination should include a pelvic examination, a Pap smear, examination of the breasts, and appropriate tests for any other forms of genital or other sexually transmitted diseases, such as gonorrhea and chlamydia laboratory evaluations, if indicated. Use of Mirena (levonorgestrel-releasing intrauterine system) in patients with vaginitis or cervicitis should be postponed until proper treatment has eradicated the infection and until it has been shown that the cervicitis is not due to gonorrhea or chlamydia [see CONTRAINDICATIONS].
• Irregular bleeding may mask symptoms and signs of endometrial polyps or cancer. Because irregular bleeding/spotting is common during the first months of Mirena (levonorgestrel-releasing intrauterine system) use, exclude endometrial pathology prior to the insertion of Mirena (levonorgestrel-releasing intrauterine system) in women with persistent or uncharacteristic bleeding. If unexplained bleeding irregularities develop during the prolonged use of Mirena (levonorgestrel-releasing intrauterine system) , appropriate diagnostic measures should be taken [see WARNINGS AND PRECAUTIONS].
• The healthcare provider should determine that the patient is not pregnant. The possibility of insertion of Mirena (levonorgestrel-releasing intrauterine system) in the presence of an existing undetermined pregnancy is reduced if insertion is performed within 7 days of the onset of a menstrual period. Mirena (levonorgestrel-releasing intrauterine system) can be replaced by a new system at any time in the cycle. Mirena (levonorgestrel-releasing intrauterine system) can be inserted immediately after first trimester abortion.
• Mirena (levonorgestrel-releasing intrauterine system) should not be inserted until 6 weeks postpartum or until involution of the uterus is complete in order to reduce the incidence of perforation and expulsion. If involution is substantially delayed, consider waiting until 12 weeks postpartum [see WARNINGS AND PRECAUTIONS].
• Patients with certain types of valvular or congenital heart disease and surgically constructed systemic-pulmonary shunts are at increased risk of infective endocarditis. Use of Mirena (levonorgestrel-releasing intrauterine system) in these patients may represent a potential source of septic emboli. Patients with known congenital heart disease who may be at increased risk should be treated with appropriate antibiotics at the time of insertion and removal.
• Patients requiring chronic corticosteroid therapy or insulin for diabetes should be monitored with special care for infection.

Mirena (levonorgestrel-releasing intrauterine system) should be used with caution in patients who have:

• Coagulopathy or are receiving 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

Insertion Precautions

• Observe strict asepsis during insertion. The presence of organisms capable of establishing PID cannot be determined by appearance, and IUD insertion may be associated with introduction of vaginal bacteria into the uterus. Administration of antibiotics may be considered, but the utility of this treatment is unknown.
• Carefully sound the uterus prior to Mirena (levonorgestrel-releasing intrauterine system) insertion to determine the degree of patency of the endocervical canal and the internal os, and the direction and depth of the uterine cavity. In occasional cases, severe cervical stenosis may be encountered. Do not use excessive force to overcome this resistance.
• Fundal positioning of Mirena (levonorgestrel-releasing intrauterine system) is important to prevent expulsion and maximize efficacy. Therefore, follow the instructions for the insertion carefully.
• If the patient develops decreased pulse, perspiration, or pallor, have her remain supine until these signs resolve. Insertion may be associated with some pain and/or bleeding. Syncope, bradycardia, or other neurovascular episodes may occur during insertion of Mirena (levonorgestrel-releasing intrauterine system) , especially in patients with a predisposition to these conditions or cervical stenosis.

Continuation and Removal

• Reexamine and evaluate patients 4 to 12 weeks after insertion and once a year thereafter, or more frequently if clinically indicated.
• If the threads are not visible, they may have retracted into the uterus or broken, or Mirena (levonorgestrel-releasing intrauterine system) may have broken, perforated the uterus, or been expelled [see WARNINGS AND PRECAUTIONS]. If the length of the threads has changed from the length at time of insertion, the system may have become displaced. Pregnancy must be excluded and the location of Mirena (levonorgestrel-releasing intrauterine system) verified, for example, by sonography, X-ray, or by gentle exploration of the uterine cavity with a probe. If Mirena (levonorgestrel-releasing intrauterine system) is displaced, remove it. A new Mirena (levonorgestrel-releasing intrauterine system) may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Mirena (levonorgestrel-releasing intrauterine system) is in place with no evidence of perforation, no intervention is indicated.
• Promptly examine users with complaints of pain, odorous discharge, unexplained bleeding [see WARNINGS AND PRECAUTIONS], fever, genital lesions or sores.
• Consider the possibility of ectopic pregnancy in the case of lower abdominal pain especially in association with missed periods or if an amenorrheic woman starts bleeding [see WARNINGS AND PRECAUTIONS].

In the event a pregnancy is confirmed during Mirena (levonorgestrel-releasing intrauterine system) use:

• Determine whether pregnancy is ectopic and, if so, take appropriate measures.
• Inform patient of the risks of leaving Mirena (levonorgestrel-releasing intrauterine system) in place or removing it during pregnancy and of the lack of data on long-term effects on the offspring of women who have had Mirena (levonorgestrel-releasing intrauterine system) in place during conception or gestation [see WARNINGS AND PRECAUTIONS].
• If possible, Mirena (levonorgestrel-releasing intrauterine system) should be removed after the patient has been warned of the risks of removal. If removal is difficult, the patient should be counseled and offered pregnancy termination.
• If Mirena (levonorgestrel-releasing intrauterine system) is left in place, the patient's course should be followed closely.

In the event of a sexually transmitted disease during Mirena (levonorgestrel-releasing intrauterine system) use:

Should the patient's relationship cease to be mutually monogamous, or should her partner become HIV positive, or acquire a sexually transmitted disease, she should be instructed to report this change to her clinician immediately. The use of a barrier method as a partial protection against acquiring sexually transmitted diseases should be strongly recommended. Removal of Mirena (levonorgestrel-releasing intrauterine system) should be considered.

Mirena (levonorgestrel-releasing intrauterine system) should be removed for the following medical reasons:

• New onset menorrhagia and/or metrorrhagia producing anemia
• Sexually transmitted disease
• Pelvic infection; endometritis
• Symptomatic genital actinomycosis
• Intractable pelvic pain
• Severe dyspareunia
• Pregnancy
• Endometrial or cervical malignancy
• Uterine or cervical perforation

Removal of the system should also be considered if any of the following conditions arise for the first time:

• Migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia
• Exceptionally severe headache
• Jaundice
• Marked increase of blood pressure
• Severe arterial disease such as stroke or myocardial infarction Removal may be associated with some pain and/or bleeding or neurovascular episodes.

Glucose Tolerance

Levonorgestrel may affect glucose tolerance, and the blood glucose concentration should be monitored in diabetic users of Mirena (levonorgestrel-releasing intrauterine system) .

Patient Counseling Information

• Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases (STDs).
• Prior to insertion, give the patient the Patient Information Booklet. She should be given the opportunity to read the information and discuss fully any questions she may have concerning Mirena (levonorgestrel-releasing intrauterine system) as well as other methods of contraception and therapies for heavy menstrual bleeding. Also, advise the patient that the prescribing information is available to her upon request.
• Inform the patient that irregular or prolonged bleeding and spotting, and/or cramps may occur during the first few weeks after insertion. If her symptoms continue or are severe she should report them to her healthcare provider.
• Instruct the patient to contact her healthcare provider if she experiences any of the following:
  • A stroke or heart attack
  • Develops very severe or migraine headaches
  • Unexplained fever
  • Yellowing of the skin or whites of the eyes, as these may be signs of serious liver problems She thinks she is pregnant
  • Pelvic pain or pain during sex
  • She or her partner becomes HIV positive
  • She might be exposed to sexually transmitted diseases (STDs)
  • Unusual vaginal discharge or genital sores
  • Severe vaginal bleeding or bleeding that lasts a long time, or if she misses a menstrual period.
  • Cannot feel Mirena (levonorgestrel-releasing intrauterine system) 's threads

Instruct the patient on how to check after her menstrual period to make certain that the threads still protrude from the cervix and caution her not to pull on the threads and displace Mirena (levonorgestrel-releasing intrauterine system) . Inform her that there is no contraceptive protection if Mirena (levonorgestrel-releasing intrauterine system) is displaced or expelled.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Long-term studies in animals to assess the carcinogenic potential of levonorgestrel releasing intrauterine system have not been performed. There is no evidence of increased risk of cancer with short-term use of progestins. There was no increase in tumorigenicity following parenteral administration of levonorgestrel to rats for 2 years at approximately 5 mcg/day, or following oral administration to dogs for 7 years at up to 0.125 mg/kg/day, or to rhesus monkeys for 10 years at up to 250 mcg/kg/day. In another 7 year dog study, oral administration of levonorgestrel at 0.5 mg/kg/day did increase the number of mammary adenomas in treated dogs compared to controls. There were no malignancies. The nonclinical doses above are respectively 16, 200, 240 and 810 times the release rate of levonorgestrel by Mirena (levonorgestrel-releasing intrauterine system) (20 mcg/day), based on body surface area [see WARNINGS AND PRECAUTIONS].

Mutagenicity

Levonorgestrel was not found to be genotoxic in the Ames assay, in vitro mammalian culture assays utilizing mouse lymphoma cells and Chinese hamster ovary cells, and in an in vivo micronucleus assay in mice.

Impairment of Fertility

There are no irreversible effects on fertility following cessation of exposures to levonorgestrel or progestins in general.

Use In Specific Populations

Pregnancy

Many studies have found no harmful effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted with progestin-only pills have not demonstrated significant adverse effects. [Also see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS.]

Nursing Mothers

In general, no adverse effects have been found on breastfeeding performance or on the health, growth, or development of the infant. However, isolated postmarketing cases of decreased milk production have been reported. Small amounts of progestins pass into the breast milk of nursing mothers, resulting in detectable steroid levels in infant serum. [Also, see WARNINGS AND PRECAUTIONS].

Pediatric Use

Safety and efficacy of Mirena (levonorgestrel-releasing intrauterine system) have been established in women of reproductive age. Use of this product before menarche is not indicated.

Geriatric Use

Mirena (levonorgestrel-releasing intrauterine system) has not been studied in women over age 65 and is not currently approved for use in this population.

Hepatic Impairment

No studies were conducted to evaluate the effect of hepatic disease on the disposition of levonorgestrel released from Mirena [see CONTRAINDICATIONS].

Renal Impairment

No studies were conducted to evaluate the effect of renal disease on the disposition of levonorgestrel released from Mirena (levonorgestrel-releasing intrauterine system) .

Last reviewed on RxList: 12/20/2010
This monograph has been modified to include the generic and brand name in many instances.