Levonorgestrel (Intrauterine)

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# Overview
Levonorgestrel (Intrauterine) is an contraceptive that is FDA approved for the prophylaxis of as method of contraception for women with heavy menstrual bleeding.   Common adverse reactions include menstrual bleeding, nausea, lower abdominal pain, fatigue, headache, and dizziness.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Mirena is indicated for intrauterine contraception for up to 5 years.
- Mirena is also indicated for the treatment of heavy menstrual bleeding in women who choose to use intrauterine contraception as their method of contraception.
- Mirena is recommended for women who have had at least one child.
- The system should be replaced after 5 years if continued use is desired.
- Mirena contains 52 mg of levonorgestrel. Initially, levonorgestrel is released at a rate of approximately 20 mcg/day. This rate decreases progressively to half that value after 5 years.
- Mirena is packaged sterile within an inserter. Information regarding insertion instructions, patient counseling and record keeping, patient follow-up, removal of Mirena and continuation of contraception after removal is provided below.
- NOTE: Mirena should be inserted by a trained healthcare provider. Healthcare providers are advised to become thoroughly familiar with the insertion instructions before attempting insertion of Mirena.
- Mirena is inserted with the provided inserter ( FIGURE 1A)  into the uterine cavity within seven days of the onset of menstruation or immediately after a first trimester abortion by carefully following the insertion instructions. It can be replaced by a new Mirena at any time during the menstrual cycle.
- Keep a copy of the consent form and lot number for your records.
- Counsel the patient on what to expect following Mirena insertion. Give the patient the Follow-up Reminder Card that is provided with the product. Discuss expected bleeding patterns during the first months of Mirena use.
- Prescribe analgesics, if indicated.
- Patients should be reexamined and evaluated 4 to 12 weeks after insertion and once a year thereafter, or more frequently if clinically indicated.
- Remove Mirena by applying gentle traction on the threads with forceps. The arms will fold upward as it is withdrawn from the uterus. Mirena should not remain in the uterus after 5 years.
- Removal may be associated with some pain and/or bleeding or neurovascular episodes.
- If the threads are not visible and Mirena is in the uterine cavity, it may be removed using a narrow forceps, such as an alligator forceps. This may require dilation of the cervical canal.
- After removal of Mirena, verify that the system is intact.
- During difficult removals, the hormone cylinder may slide over and cover the horizontal arms. This situation generally does not require further intervention once the system is verified to be intact.
- If Mirena is removed mid-cycle and the woman has had intercourse within the preceding week, she is at a risk of pregnancy unless a new Mirena is inserted immediately following removal.
- You may insert a new Mirena immediately following removal.
- If a patient with regular cycles wants to start a different birth control method, remove Mirena during the first 7 days of the menstrual cycle and start the new method.
- If a patient with irregular cycles or amenorrhea wants to start a different birth control method, or if you remove Mirena after the seventh day of the menstrual cycle, start the new method at least 7 days before removal.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Levonorgestrel (Intrauterine) in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Levonorgestrel (Intrauterine) in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Levonorgestrel (Intrauterine) in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Levonorgestrel (Intrauterine) in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Levonorgestrel (Intrauterine) in pediatric patients.

# Contraindications
- Evaluate women who become pregnant while using Mirena for ectopic pregnancy. Up to half of pregnancies that occur with Mirena 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 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 is unknown. Clinical trials of Mirena excluded women with a history of ectopic pregnancy.
- If pregnancy should occur with Mirena in place, Mirena should be removed. Removal or manipulation of Mirena may result in pregnancy loss. In the event of an intrauterine pregnancy with Mirena, consider the following:
- In patients becoming pregnant with an IUD in place, septic abortionwith septicemia, septic shock, and deathmay occur.
- If a woman becomes pregnant with Mirena in place and if Mirena cannot be removed or the woman chooses not to have it removed, she should be warned that failure to remove Mirena 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 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 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 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 is unknown.
- As of September 2006, 9 cases of Group A streptococcal sepsis (GAS) out of an estimated 9.9 million Mirena 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 is essential. GAS sepsis may also occur postpartum, after surgery, and from wounds.
- Mirena 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). A decision to use Mirena 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 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 users
- All women who choose Mirena 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.
- Following a diagnosis of PID, or suspected PID, bacteriologic specimens should be obtained and antibiotic therapy should be initiated promptly. Removal of Mirena 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.
- Mirena 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 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 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.
- 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.
- Embedment of Mirena in the myometrium may occur. Embedment may decrease contraceptive effectiveness and result in pregnancy. An embedded Mirena should be removed. Embedment can result in difficult removal and, in some cases surgical removal may be necessary.
- 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. Mirena 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.
- Clinical trials with Mirena excluded breast-feeding women. An interim analysis from a large postmarketing safety study shows an increased risk of perforation in lactating women. The risk of perforation may be increased in women with fixed retroverted uteri, and during the postpartum period. To decrease the risk of perforation postpartum, Mirena 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 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.
- Partial or complete expulsion of Mirena may occur.
- 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. As menstrual flow typically decreases after the first 3 to 6 months of Mirena use, an increase of menstrual flow may be indicative of an expulsion. If expulsion has occurred, Mirena may be replaced within 7 days of a menstrual period after pregnancy has been ruled out.
- Since the contraceptive effect of Mirena is mainly due to its local effect, ovulatory cycles with follicular rupture usually occur in women of fertile age using Mirena. 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. 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.
- 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. 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.
- 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.
- 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 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 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.
- Irregular bleeding may mask symptoms and signs of endometrial polyps or cancer. Because irregular bleeding/spotting is common during the first months of Mirena use, exclude endometrial pathology prior to the insertion of Mirena in women with persistent or uncharacteristic bleeding. If unexplained bleeding irregularities develop during the prolonged use of Mirena, appropriate diagnostic measures should be taken.
- The healthcare provider should determine that the patient is not pregnant. The possibility of insertion of Mirena 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 can be replaced by a new system at any time in the cycle. Mirena can be inserted immediately after first trimester abortion.
- Mirena 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.
- 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 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 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.
- 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 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 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, especially in patients with a predisposition to these conditions or cervical stenosis.
- 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 may have broken, perforated the uterus, or been expelled. 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 verified, for example, by sonography, X-ray, or by gentle exploration of the uterine cavity with a probe. If Mirena is displaced, remove it. A new Mirena may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Mirena is in place with no evidence of perforation, no intervention is indicated.
- Promptly examine users with complaints of pain, odorous discharge, unexplained bleeding, 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.
- In the event a pregnany is confirmed during Mirena use:
- Determine whether pregnancy is ectopic and, if so, take appropriate measures.
- Inform patient of the risks of leaving Mirena 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 in place during conception or gestation.
- If possible, Mirena 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 is left in place, the patient's course should be followed closely.
- In the event of a sexually transmitted disease during Mirena 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 should be considered.
- Mirena 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.
- Levonorgestrel may affect glucose tolerance, and the blood glucose concentration should be monitored in diabetic users of Mirena.

# Warnings
- Evaluate women who become pregnant while using Mirena for ectopic pregnancy. Up to half of pregnancies that occur with Mirena 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 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 is unknown. Clinical trials of Mirena excluded women with a history of ectopic pregnancy.
- If pregnancy should occur with Mirena in place, Mirena should be removed. Removal or manipulation of Mirena may result in pregnancy loss. In the event of an intrauterine pregnancy with Mirena, consider the following:
- In patients becoming pregnant with an IUD in place, septic abortionwith septicemia, septic shock, and deathmay occur.
- Continuation of pregnancy
- If a woman becomes pregnant with Mirena in place and if Mirena cannot be removed or the woman chooses not to have it removed, she should be warned that failure to remove Mirena 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.
- When pregnancy continues with Mirena 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 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 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 is unknown.
- As of September 2006, 9 cases of Group A streptococcal sepsis (GAS) out of an estimated 9.9 million Mirena 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 is essential. GAS sepsis may also occur postpartum, after surgery, and from wounds.
- Mirena 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). A decision to use Mirena must include consideration of the risks of PID.
- PID is often associated with a sexually transmitted disease, and Mirena 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.
- All women who choose Mirena 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.
- PID may be asymptomatic but still result in tubal damage and its sequelae.
- Following a diagnosis of PID, or suspected PID, bacteriologic specimens should be obtained and antibiotic therapy should be initiated promptly. Removal of Mirena 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.
- Mirena 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 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 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.
- 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.
- Embedment of Mirena in the myometrium may occur. Embedment may decrease contraceptive effectiveness and result in pregnancy. An embedded Mirena should be removed. Embedment can result in difficult removal and, in some cases surgical removal may be necessary.
- 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. Mirena 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.
- Clinical trials with Mirena excluded breast-feeding women. An interim analysis from a large postmarketing safety study shows an increased risk of perforation in lactating women. The risk of perforation may be increased in women with fixed retroverted uteri, and during the postpartum period. To decrease the risk of perforation postpartum, Mirena 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 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.
- Partial or complete expulsion of Mirena may occur.
- 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. As menstrual flow typically decreases after the first 3 to 6 months of Mirena use, an increase of menstrual flow may be indicative of an expulsion. If expulsion has occurred, Mirena may be replaced within 7 days of a menstrual period after pregnancy has been ruled out.
- Since the contraceptive effect of Mirena is mainly due to its local effect, ovulatory cycles with follicular rupture usually occur in women of fertile age using Mirena. 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. 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.
- 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. 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.
- 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.
- 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 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 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.
- Irregular bleeding may mask symptoms and signs of endometrial polyps or cancer. - Because irregular bleeding/spotting is common during the first months of Mirena use, exclude endometrial pathology prior to the insertion of Mirena in women with persistent or uncharacteristic bleeding. If unexplained bleeding irregularities develop during the prolonged use of Mirena, appropriate diagnostic measures should be taken.
- The healthcare provider should determine that the patient is not pregnant. The possibility of insertion of Mirena 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 can be replaced by a new system at any time in the cycle.
- Mirena can be inserted immediately after first trimester abortion.
- Mirena 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.
- 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 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 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.
- 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 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 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, especially in patients with a predisposition to these conditions or cervical stenosis.
- 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 may have broken, perforated the uterus, or been expelled. 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 verified, for example, by sonography, X-ray, or by gentle exploration of the uterine cavity with a probe. If Mirena is displaced, remove it. A new Mirena may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Mirena is in place with no evidence of perforation, no intervention is indicated.
- Promptly examine users with complaints of pain, odorous discharge, unexplained bleeding, 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.
- In the event a pregnancy is confirmed during Mirena use:
- Determine whether pregnancy is ectopic and, if so, take appropriate measures.
- Inform patient of the risks of leaving Mirena 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 in place during conception or gestation.
- If possible, Mirena 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 is left in place, the patient's course should be followed closely.
- In the event of a sexually transmitted disease during Mirena 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 should be considered.
- Mirena 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.
- Levonorgestrel may affect glucose tolerance, and the blood glucose concentration should be monitored in diabetic users of Mirena.

# Adverse Reactions

## Clinical Trials Experience
- Ectopic Pregnancy
- Intrauterine Pregnancy
- Group A streptococcal sepsis (GAS)
- Pelvic Inflammatory Disease
- Embedment

### Perforation
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The data provided reflect the experience with the use of Mirena in the adequate and well-controlled studies for contraception (n=2,339) and heavy menstrual bleeding (n=80). For the contraception indication, Mirena was compared to a copper IUD (n=1,855), to another formulation of levonorgestrel intrauterine system (n=390) and to a combined oral contraceptive (n=94) in women 18 to 35 years old. The data cover more than 92,000 woman-months of exposure. For the treatment of heavy menstrual bleeding indication (n=80), the subjects included women aged 26 to 50 with confirmed heavy bleeding and exposed for a median of 183 treatment days of Mirena (range 7 to 295 days). The frequencies of reported adverse drug reactions represent crude incidences.
- The adverse reactions seen across the 2 indications overlapped, and are reported using the frequencies from the contraception studies.
- The most common adverse reactions (5% users) are uterine/vaginal bleeding alterations (51.9%), amenorrhea (23.9%), intermenstrual bleeding and spotting (23.4%), abdominal/pelvic pain (12.8%), ovarian cysts (12%), headache/migraine (7.7%), acne (7.2%), depressed/altered mood (6.4%), menorrhagia (6.3%), breast tenderness/pain (4.9%), vaginal discharge (4.9%) and IUD expulsion (4.9%).
- Other relevant adverse reactions occurring in <5% of subjects include nausea], nervousness, vulvovaginitis, dysmenorrhea, back pain, weight increase, decreased libido, cervicitis/Papanicolaou smear normal/class II, hypertension, dyspareunia, anemia, alopecia, skin disorders including eczema, pruritus, rash and urticaria, abdominal distention, hirsutism and edema.

## Postmarketing Experience
There is limited information regarding Levonorgestrel (Intrauterine) Postmarketing Experience in the drug label.

# Drug Interactions
- Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the serum concentrations of progestins.
- Some drugs or herbal products that may decrease the serum concentration of levonorgestrel include:
- Barbiturates
- Bosentan
- Carbamazepine
- Felbamate
- Griseofulvin
- Oxcarbazepine
- Phenytoin
- Rifampin
- St. Johns wort
- Topiramate.
- Significant changes (increase or decrease) in the serum concentrations of the progestin have been noted in some cases of co-administration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.
- Consult the labeling of all concurrently used drugs to obtain further information about interactions with Mirena or the potential for enzyme alterations.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- 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.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Levonorgestrel (Intrauterine) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Levonorgestrel (Intrauterine) during labor and delivery.

### 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.

### Pediatric Use
There is no FDA guidance on the use of Levonorgestrel (Intrauterine) with respect to pediatric patients.

### Geriatic Use
There is no FDA guidance on the use of Levonorgestrel (Intrauterine) with respect to geriatric patients.

### Gender
There is no FDA guidance on the use of Levonorgestrel (Intrauterine) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Levonorgestrel (Intrauterine) with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Levonorgestrel (Intrauterine) in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Levonorgestrel (Intrauterine) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Levonorgestrel (Intrauterine) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Levonorgestrel (Intrauterine) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intrauterine

### Monitoring
There is limited information regarding Monitoring of Levonorgestrel (Intrauterine) in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Levonorgestrel (Intrauterine) in the drug label.

# Overdosage
There is limited information regarding Levonorgestrel (Intrauterine) overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
- The local mechanism by which continuously released levonorgestrel enhances contraceptive effectiveness of Mirena has not been conclusively demonstrated. Studies of Mirena prototypes have suggested several mechanisms that prevent pregnancy: thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, and alteration of the endometrium.

## Structure

## Pharmacodynamics
- Mirena has mainly local progestogenic effects in the uterine cavity. The high local levels of levonorgestrel1 lead to morphological changes including stromal pseudodecidualization, glandular atrophy, a leukocytic infiltration and a decrease in glandular and stromal mitoses.
- Ovulation is inhibited in some women using Mirena. In a 1-year study approximately 45% of menstrual cycles were ovulatory and in another study after 4 years 75% of cycles were ovulatory.

## Pharmacokinetics
- Low doses of levonorgestrel are administered into the uterine cavity with the Mirena intrauterine delivery system. Initially, levonorgestrel is released at a rate of approximately 20 mcg/day. This rate decreases progressively to half that value after 5 years. A stable serum concentration, without peaks and troughs, of levonorgestrel of 150200 pg/mL occurs after the first few weeks following insertion of Mirena. Levonorgestrel concentrations after long-term use of 12, 24, and 60 months were 18066 pg/mL, 192140 pg/mL, and 15959 pg/mL, respectively.
- The apparent volume of distribution of levonorgestrel is reported to be approximately 1.8 L/kg. It is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin.
- Following absorption, levonorgestrel is conjugated at the 17-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in serum. Significant amounts of conjugated and unconjugated 3, 5- tetrahydrolevonorgestrel are also present in serum, along with much smaller amounts of 3, 5-tetrahydrolevonorgestrel and 16hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for wide individual variations in levonorgestrel concentrations seen in individuals using levonorgestrelcontaining contraceptive products.
- About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The elimination half-life of levonorgestrel after daily oral doses is approximately 17 hours.
- Pediatric: Safety and efficacy of Mirena have been established in women of reproductive age. Use of this product before menarche is not indicated.
- Geriatric: Mirena has not been studied in women over age 65 and is not currently approved for use in this population.
- Race: No studies have evaluated the effect of race on pharmacokinetics of Mirena.
- Hepatic Impairment: No studies were conducted to evaluate the effect of hepatic disease on the disposition of Mirena.
- Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of Mirena.
- No drug-drug interaction studies were conducted with Mirena.

## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Levonorgestrel (Intrauterine) in the drug label.

# Clinical Studies
- Mirena has been studied for safety and efficacy in two large clinical trials in Finland and Sweden. In study sites having verifiable data and informed consent, 1,169 women 18 to 35 years of age at enrollment used Mirena for up to 5 years, for a total of 45,000 women-months of exposure. Subjects had previously been pregnant, had no history of ectopic pregnancy, had no history of pelvic inflammatory disease over the preceding 12 months, were predominantly Caucasian, and over 70% of the participants had previously used IUDs (intrauterine devices). The reported 12-month pregnancy rates were less than or equal to 0.2 per 100 women (0.2%) and the cumulative 5-year pregnancy rate was approximately 0.7 per 100 women (0.7%).
- About 80% of women wishing to become pregnant conceived within 12 months after removal of implant.
- The efficacy of Mirena in the treatment of heavy menstrual bleeding was studied in a randomized, open-label, active-control, parallel-group trial comparing Mirena (n=79) to an approved therapy, medroxyprogesterone acetate (MPA) (n=81), over 6 cycles. The subjects included reproductive-aged women in good health, with no contraindications to the drug products and with confirmed heavy menstrual bleeding ( 80 mL menstrual blood loss ) determined using the alkaline hematin method. Excluded were women with organic or systemic conditions that may cause heavy uterine bleeding (except small fibroids, with total volume not > 5 mL). Treatment with Mirena showed a statistically significantly greater reduction in MBL (see Figure 10) and a statistically significantly greater number of subjects with successful treatment (see Figure 11). Successful treatment was defined as proportion of subjects with (1) end-of-study MBL < 80 mL and (2) a  50% decrease in MBL from baseline to end-of-study.

# How Supplied
- Mirena (levonorgestrel-releasing intrauterine system), containing a total of 52 mg levonorgestrel, is available in a carton of one sterile unit NDC# 50419-421-01. Each Mirena is packaged together with an inserter in a thermoformed blister package with a peelable lid.
- Mirena is supplied sterile. Mirena is sterilized with ethylene oxide. Do not resterilize. For single use only. Do not use if the inner package is damaged or open. Insert before the end of the month shown on the label.

## Storage
- Store at 25C (77F); with excursions permitted between 1530C (5986F)

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Levonorgestrel (Intrauterine) in the drug label.

# Precautions with Alcohol
- Alcohol-Levonorgestrel (Intrauterine) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- MIRENA

# Look-Alike Drug Names
There is limited information regarding Levonorgestrel (Intrauterine) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price