Mirena

Mirena is the brand name of the levonorgestrel-releasing intrauterine system, which is used to prevent pregnancy.

It may also be used to treat heavy menstrual bleeding in women who want to prevent pregnancy.

Levonorgestrel, the active ingredient in contraceptives known as “morning-after pills,” is a form of the hormone progestin and is in a class of medicines known as hormonal contraceptives.

It works by thinning the lining of the uterus, thickening the mucus of the cervix, and preventing sperm from moving and surviving in the uterus.

The levonorgestrel-releasing intrauterine system may also prevent ovulation in some women.

Mirena, which is made of soft plastic, is inserted into the uterus by a healthcare provider and can be left in place for up to five years.

It can be removed by your doctor any time you decide you want to become pregnant and must be replaced with a new device after five years.

The manufacturer of Mirena says the system should only be used by women who have given birth to at least one child.

However, some experts believe women who have not given birth can use Mirena.

Mirena Warnings

Mirena is an effective method of birth control, but it does not protect against sexually-transmitted diseases.

You should not have Mirena inserted if you are pregnant or plan to become pregnant.

Your doctor will give you a pregnancy test before inserting the intrauterine system.

It’s unlikely that you will become pregnant while having Mirena in place, but if you do, you’re at an increased risk for having an ectopic pregnancy (a pregnancy that develops outside the uterus).

You’re also at a higher risk for severe infection, miscarriage, pre-term labor, or death if your pregnancy continues with your Mirena in place.

There's a risk that the Mirena device could attach to or move through the wall of your uterus. There's a greater chance this will happen if you are breastfeeding, so be sure to tell your doctor if you are nursing.

However, if you are breastfeeding more than six weeks after giving birth, your doctor will probably tell you it’s OK to have the Mirena inserted.

Mirena may increase your chances of developing pelvic inflammatory disease (PID). This condition can cause infertility, ectopic pregnancy, chronic pain, or even death.

PID happens to less than 1 percent of users, but the risk of developing it is greater if you or your partner have more than one sexual partner. You should tell your doctor if either of you have multiple sexual partners.

Call your doctor right away if you experience severe pain during the first few hours after your Mirena device is inserted. Pain could be a symptom of a serious infection.

Mirena may also increase your risk of developing an ovarian cyst.

This type of cyst can cause pain but usually goes away in a couple of months. In rare instances, surgery is required to remove the cyst.

You will likely experience changes in your menstrual cycle with Mirena in place.

Your periods may be irregular, longer, or heavier during the first 3 to 6 months after the device is inserted.

You also may experience spotting between your periods. Over time, your cycles will probably become lighter and shorter.

If your period stops, it will return once the device is removed.

You should call your doctor if you were having regular periods but have not menstruated in six weeks or if your bleeding becomes heavy after being light for some time.

Before having Mirena inserted, you should tell your doctor if you have ever had:

• Breast cancer
• Uterine fibroids or any condition that affects the shape of the inside of your uterus
• Uterine cancer or cervical cancer
• An abnormal Pap smear
• Abnormal vaginal bleeding
• Liver disease or tumors
• An untreated vaginal or cervical infection
• PID
• A stroke
• A heart attack or heart disease
• Slow heart beat
• High blood pressure
• Diabetes
• Severe headaches or migraines
• Any condition that causes you to faint
• A blood clotting problem
• Seizures
• An ectopic pregnancy
• Fallopian tube surgery
• Any condition that affects your immune system, such as leukemia or HIV/AIDS

You should also tell your physician if you have had a serious infection after a pregnancy or an abortion in the past three months.

Pregnancy and Mirena

If you become pregnant while the Mirena device is in place, call your doctor right way and discuss the risks of removing the system.

Levonorgestrel is a female hormone. This hormone can cause changes in your cervical mucus and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus.

Levonorgestrel intrauterine system is a plastic device that contains the hormone levonorgestrel. This device is placed in the uterus where it slowly releases the hormone to prevent pregnancy for up to 5 years. Levonorgestrel intrauterine system is meant for use in a woman who has had at least one child and is in a stable sexual relationship with someone who has no other sexual partners.

Levonorgestrel intrauterine system is also used in women who have heavy menstrual bleeding and choose to use an intrauterine form of birth control.

Levonorgestrel is a progestin hormone and does not contain estrogen. The intrauterine device releases levonorgestrel into the uterus, but only small amounts of the hormone reach your blood stream.

Levonorgestrel intrauterine system may also be used for other purposes not listed in this medication guide.

• Bayer Healthcare Pharmaceuticals Inc.

You should not use this intrauterine device if you have abnormal vaginal bleeding, a pelvic infection, certain other problems with your uterus or cervix, or if you have breast or uterine cancer, liver disease or liver tumor, or a weak immune system.

Do not use during pregnancy. Call your doctor if you miss a period or think you might be pregnant.

Avoid having more than one sexual partner. The IUD can increase your risk of developing a serious pelvic infection, which is often caused by sexually transmitted disease. Levonorgestrel intrauterine system will not protect you from sexually transmitted diseases, including HIV and AIDS. Using a condom is the only way to help protect yourself from these diseases.

Call your doctor if your sexual partner develops HIV or a sexually transmitted disease, or if you have any change in sexual relationships.

In the U.S.

• Kyleena
• Liletta
• Mirena
• Skyla

Available Dosage Forms:

• Insert, Extended Release

Therapeutic Class: Contraceptive, Local

Pharmacologic Class: Progestin

Levonorgestrel-releasing intrauterine system is a device that contains the female hormone, levonorgestrel. It is placed in the uterus (womb) where it slowly releases the hormone to prevent pregnancy for up to 3 years for Liletta™ or Skyla™ or up to 5 years for Kyleena™ or Mirena®. It works by stopping a woman's egg from fully developing each month. The egg can no longer accept a sperm and fertilization (pregnancy) is prevented.

Levonorgestrel-releasing intrauterine system is also used to treat heavy menstrual bleeding in women who choose this device as their method for birth control.

This medicine is to be given only by or under the supervision of your doctor.

Ectopic Pregnancy

Evaluate women for ectopic pregnancy if they become pregnant with Mirena in place because the likelihood of a pregnancy being ectopic is increased with Mirena. Up to half of pregnancies that occur with Mirena in place are likely to be ectopic. Also 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.

The incidence of ectopic pregnancy in clinical trials with Mirena, which excluded women with a history of ectopic pregnancy, was approximately 0.1% per year. The risk of ectopic pregnancy, in women who have a history of ectopic pregnancy and use Mirena is unknown. Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection carry a higher risk of ectopic pregnancy. Ectopic pregnancy may result in loss of fertility.

Intrauterine Pregnancy

If pregnancy occurs while using Mirena, remove Mirena because leaving it in place may increase the risk of spontaneous abortion and preterm labor. Removal of Mirena or probing of the uterus may also result in spontaneous abortion. In the event of an intrauterine pregnancy with Mirena, consider the following:

In patients becoming pregnant with an IUD in place, septic abortion - with septicemia, septic shock, and death - may 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, warn her that failure to remove Mirena increases the risk of miscarriage, sepsis, premature labor and premature delivery. Follow her pregnancy closely and advise her to report immediately any symptom that suggests complications of the pregnancy.

When pregnancy continues with Mirena in place, long-term effects on the offspring are unknown. Congenital anomalies in live births have occurred infrequently. No clear trend towards specific anomalies has been observed. Because of the local exposure of the fetus to LNG, 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.

Sepsis

Severe infection or sepsis, including Group A streptococcal sepsis (GAS), have been reported following insertion of Mirena. 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 in order to minimize serious infections such as GAS.

Pelvic Infection

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 [see Contraindications (4)]. IUDs have been associated with an increased risk of PID, most likely due to organisms being introduced into the uterus during insertion. In clinical trials, total combined upper genital infections were reported in 3.5% of Mirena users. More specifically, endometritis was reported in 2.1%, PID in 0.6%, and all other upper genital infections in ≤0.5% of women overall. These infections occurred more frequently within the first year. In a clinical trial with other IUDs1 and a clinical trial with an IUD similar to Mirena, the highest rate occurred within the first month after insertion.

Promptly examine users with complaints of lower abdominal or pelvic pain, odorous discharge, unexplained bleeding, fever, genital lesions or sores. Remove Mirena in cases of recurrent endometritis or PID, or if an acute pelvic infection is severe or does not respond to treatment.

Women at increased risk for PID

PID is often associated with a sexually transmitted infection, and Mirena does not protect against sexually transmitted infection. 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. In particular, ascertain whether the woman is at increased risk of infection (for example, leukemia, acquired immune deficiency syndrome [AIDS], IV drug abuse).

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 after initiation of antibiotic therapy is usually appropriate. Guidelines for PID treatment are available from the Centers for Disease Control (CDC), Atlanta, Georgia.

Actinomycosis

Actinomycosis has been associated with IUDs. Symptomatic women should have Mirena removed and should receive antibiotics. The significance of actinomyces-like organisms on Pap smear in an asymptomatic IUD user is unknown, and so this finding alone does not always require Mirena removal and treatment. When possible, confirm a Pap smear diagnosis with cultures.

Irregular Bleeding and Amenorrhea

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 [see Clinical Studies (14.1)].

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 (14.2)].

Perforation

Perforation (total or partial, including penetration/embedment of Mirena in the uterine wall or cervix) may occur most often during insertion, although the perforation may not be detected until sometime later. Perforation may reduce contraceptive efficacy and result in pregnancy. The incidence of perforation during clinical trials, which excluded breast-feeding women, was < 0.1%.

If perforation occurs, locate and remove Mirena. Surgery may be required. Delayed detection or removal of Mirena in case 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 if Mirena is inserted when the uterus is fixed retroverted or not completely involuted. Delay Mirena insertion a minimum of six weeks or until involution is complete following a delivery or a second trimester abortion.

A large postmarketing safety study conducted in Europe over a 1-year observational period reported that lactation at the time of insertion of an IUD/IUS was associated with an increased risk of perforation. For Mirena users, the incidence of uterine perforation was reported as 6.3 per 1,000 insertions for lactating women, compared to 1.0 per 1,000 insertions for non-lactating women.

Expulsion

Partial or complete expulsion of Mirena may occur resulting in the loss of contraceptive protection. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. Mirena typically decreases menstrual bleeding over time; therefore, an increase of menstrual bleeding may be indicative of an expulsion. The risk of expulsion may be increased when the uterus is not completely involuted. In clinical trials, a 4.5% expulsion rate was reported over the 5-year study duration.

Delay Mirena insertion a minimum of six weeks or until uterine involution is complete following a delivery or a second trimester abortion. Remove a partially expelled Mirena. If expulsion has occurred, a new Mirena can be inserted any time the provider can be reasonably certain the woman is not pregnant..

Ovarian Cysts

Because the contraceptive effect of Mirena is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age using Mirena. Sometime atresia of the follicle is delayed and the follicle may continue to grow. Ovarian cysts have been reported in approximately 8% of women using Mirena. Most of these cysts are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia.

In most cases the ovarian cysts disappear spontaneously during two to three months observation. Evaluate persistent ovarian cysts. 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 some breast cancers are hormone-sensitive [see Contraindications (4)].

Spontaneous reports of breast cancer have been received during postmarketing experience with Mirena. Observational studies of the risk of breast cancer with use of a LNG-releasing IUS do not provide conclusive evidence of increased risk.

Clinical Considerations for Use and Removal

Use Mirena with caution after careful assessment if any of the following conditions exist, and consider removal of the system if any of them arise during use:

In addition, consider removing Mirena if any of the following conditions arise during use [see Contraindications (4)]:

If the threads are not visible or are significantly shortened they may have broken or retracted into the cervical canal or uterus. Consider the possibility that the system may have been displaced (for example, expelled or perforated the uterus) [see Warnings and Precautions (5.6, 5.7)]. Exclude pregnancy and verify the location of Mirena, for example, by sonography, X-ray, or by gentle exploration of the cervical canal with a suitable instrument. 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.

Pregnancy

The use of Mirena is contraindicated in pregnancy or with a suspected pregnancy because there is no need for pregnancy prevention in a woman who is already pregnant and Mirena may cause adverse pregnancy outcomes [see Contraindications (4), Warnings and Precautions (5.1, 5.2)]. If a woman becomes pregnant with Mirena in place, the likelihood of ectopic pregnancy is increased and there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery. Remove Mirena, if possible, if pregnancy occurs in a woman using Mirena. If Mirena cannot be removed, follow the pregnancy closely [see Warnings and Precautions (5.1, 5.2)].

Studies report no adverse effects on fetal and infant development associated with long-term use of contraceptive doses of oral progestins in a pregnant woman. However, there have been reported cases of masculinization of the external genitalia of the female fetus following exposure to progestins at doses greater than those currently used for oral contraception.

Lactation

Published studies report the presence of LNG in human milk. Small amounts of progestins (approximately 0.1% of the total maternal doses) were detected in the breast milk of nursing mothers who used Mirena, resulting in exposure of LNG to the breastfed infants. There are no reports of adverse effects in breastfed infants with maternal use of progestin-only contraceptives. Isolated cases of decreased milk production have been reported with Mirena. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Mirena and any potential adverse effects on the breastfed child from Mirena or from the underlying maternal condition.

Pediatric Use

Safety and efficacy of Mirena have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal females under the age of 18 as for users 18 years and older. Use of this product before menarche is not indicated.

Geriatric Use

Mirena has not been studied in women over age 65 and is not approved for use in this population.

Hepatic Impairment

No studies were conducted to evaluate the effect of hepatic disease on the disposition of LNG released from Mirena [see Contraindications (4)].

Renal Impairment

No studies were conducted to evaluate the effect of renal disease on the disposition of LNG released from Mirena.

Clinical Trials on Contraception

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. Of these, 5.6% (66) were nulliparous women. 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 Mirena.

Clinical Trial on Heavy Menstrual Bleeding

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 [MBL]) 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 12) and a statistically significantly greater number of subjects with successful treatment (see Figure 13). 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.

Figure 12 Median Menstrual Blood Loss (MBL) by Time and Treatment

Figure 13 Proportion of Subjects with Successful Treatment

Figure 13 Proportion of Subjects with Successful Treatment

Mirena (levonorgestrel-releasing intrauterine system), containing a total of 52 mg LNG, is available in a carton of one sterile unit NDC# 50419-423-01.

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.

Store at 25°C (77°F); with excursions permitted between 15–30°C (59–86°F) [see USP Controlled Room Temperature].

The Mirena intrauterine device (IUD) contains levonorgestrel, a female hormone that can cause changes in your cervical mucus and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus. Mirena is a plastic device that is placed in the uterus where it slowly releases the hormone to prevent pregnancy up to 5 years.

Mirena is used to prevent pregnancy for up to 5 years. It can be used whether or not you have had a child. Mirena is also used to treat heavy menstrual bleeding in women who choose to use an intrauterine form of birth control.

Levonorgestrel is a progestin hormone and does not contain estrogen. The intrauterine device (IUD) releases levonorgestrel in the uterus, but only small amounts of the hormone reach the bloodstream. Mirena should not be used as emergency birth control.

Usual Adult Dose for Contraception:

Contraception:
Mirena: One 52 mg intrauterine device inserted within seven days of the onset of menstruation or immediately after first-trimester abortion. One device is effective for 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.

Other drugs may interact with levonorgestrel, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.