Label: MIRENA- levonorgestrel intrauterine device
- NDC Code(s): 50419-423-01, 50419-423-08
- Packager: Bayer HealthCare Pharmaceuticals Inc.
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: New Drug Application
Updated August 20, 2020
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use MIRENA safely and effectively. See full prescribing information for MIRENA.
MIRENA (levonorgestrel-releasing intrauterine system)
Initial U.S. Approval: 2000
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
- Initial release rate of levonorgestrel (LNG) is 20 mcg/day; this rate is reduced to about 10 mcg/day after 5 and 9 mcg/day after 6 years. (2.1)
- To be inserted by a trained healthcare provider using strict aseptic technique. Follow insertion instructions exactly as described. (2.2)
- Patient should be re-examined and evaluated 4 to 6 weeks after insertion; then, yearly or more often if indicated. (2.3)
DOSAGE FORMS AND STRENGTHS
- One sterile intrauterine system consisting of a T-shaped polyethylene frame with a steroid reservoir containing 52 mg levonorgestrel packaged within a sterile inserter (3)
- Pregnancy or suspicion of pregnancy. Cannot be used for post-coital contraception (4).
- Congenital or acquired uterine anomaly if it distorts the uterine cavity (4)
- Acute pelvic inflammatory disease (PID) or a history of PID unless there has been a subsequent intrauterine pregnancy (4)
- Postpartum endometritis or infected abortion in the past 3 months (4)
- Known or suspected uterine or cervical malignancy (4)
- Known or suspected breast cancer or other progestin-sensitive cancer (4)
- Uterine bleeding of unknown etiology (4)
- Untreated acute cervicitis or vaginitis or other lower genital tract infections (4)
- Acute liver disease or liver tumor (benign or malignant) (4)
- Increased susceptibility to pelvic infection (4)
- A previous intrauterine device (IUD) that has not been removed (4)
- Hypersensitivity to any component of Mirena (4)
WARNINGS AND PRECAUTIONS
- Remove Mirena if pregnancy occurs with Mirena in place. If pregnancy occurs, there is increased risk of ectopic pregnancy including loss of fertility, pregnancy loss, septic abortion (including septicemia, shock and death), and premature labor and delivery. (5.1, 5.2)
- Group A streptococcal infection has been reported; strict aseptic technique is essential during insertion. (5.3)
- Before using Mirena, consider the risks of PID. (5.4)
- Bleeding patterns become altered, may remain irregular and amenorrhea may ensue. (5.5)
- Perforation may occur and may reduce contraceptive effectiveness. Risk is increased if inserted in lactating women and may be increased if inserted in women with fixed retroverted uteri or postpartum. (5.6)
- Partial or complete expulsion may occur. (5.7)
- Evaluate persistent enlarged ovarian follicles or ovarian cysts. (5.8)
The most common adverse reactions (≥10% users) are alterations of menstrual bleeding patterns, abdominal/pelvic pain, amenorrhea, headache/migraine, genital discharge, and vulvovaginitis. (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
- Drugs or herbal products that induce certain enzymes, such as CYP3A4, may decrease the serum concentration of progestins. (7)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Table of Contents
FULL PRESCRIBING INFORMATION: CONTENTS*
- Sections or subsections omitted from the full prescribing information are not listed.
1 INDICATIONS AND USAGE
Mirena is indicated for prevention of pregnancy for up to 6 years; replace after the end of the sixth year.
1.2 Heavy Menstrual Bleeding
Mirena is indicated for the treatment of heavy menstrual bleeding for up to 5 years in women who choose to use intrauterine contraception as their method of contraception; replace after the end of the fifth year if continued treatment of heavy menstrual bleeding is needed.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Over Time
Mirena contains 52 mg of levonorgestrel (LNG). Initially, LNG is released at a rate of approximately 20 mcg/day. This rate decreases progressively to approximately 10 mcg/day after 5 years and 9 mcg/day after 6 years.
For contraception, remove Mirena by the end of the sixth year and replace at the time of removal with a new Mirena if continued use is desired.
For treatment of heavy menstrual bleeding, replace Mirena by the end of the fifth year if continued use is needed because data on use in this indication beyond 5 years are limited.
Mirena is supplied in a sterile package within an inserter that enables single-handed loading (see Figure 1). Do not open the package until required for insertion [see Description (11.2)]. Do not use if the seal of the sterile package is broken or appears compromised. Use strict aseptic techniques throughout the insertion procedure [see Warnings and Precautions (5.3)].
2.2 Insertion Instructions
- A complete medical and social history should be obtained to determine conditions that might influence the selection of a levonorgestrel-releasing intrauterine system (LNG IUS) for contraception. If indicated, perform a physical examination, and appropriate tests for any forms of genital or other sexually transmitted infections. [See Contraindications (4) and Warnings and Precautions (5.10).]
- Follow the insertion instructions exactly as described in order to ensure proper placement and avoid premature release of Mirena from the inserter. Once released, Mirena cannot be re-loaded.
- Mirena should be inserted by a trained healthcare provider. Healthcare providers should become thoroughly familiar with the insertion instructions before attempting insertion of Mirena.
- Insertion may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, bradycardia), or with seizure in an epileptic patient, especially in patients with a predisposition to these symptoms. Consider administering analgesics prior to insertion.
Timing of Insertion
Table 1: When to Insert Mirena
Starting Mirena in women not currently using hormonal or intrauterine contraception
Mirena can be inserted any time the provider can be reasonably certain the woman is not pregnant. Consider the possibility of ovulation and conception prior to initiation of this product [see Contraindications (4)].
If Mirena is inserted during the first seven days of the menstrual cycle or immediately after a first trimester abortion, back up contraception is not needed.
If Mirena is not inserted during the first seven days of the menstrual cycle, a barrier method of contraception should be used or the patient should abstain from vaginal intercourse for seven days to prevent pregnancy.
Switching to Mirena from an oral, transdermal or vaginal hormonal contraceptive
Mirena may be inserted at any time, including during the hormone-free interval of the previous method.
If inserted during active use of the previous method, continue that method for 7 days after Mirena insertion or until the end of the current treatment cycle.
If the woman was using continuous hormonal contraception, discontinue that method seven days after Mirena insertion.
Switching to Mirena from an injectable progestin contraceptive
Mirena may be inserted at any time; a back-up method of contraception (such as condoms or spermicide) should also be used for 7 days if Mirena is inserted more than 3 months (13 weeks) after the last injection.
Switching to Mirena from a contraceptive implant or another IUS
Insert Mirena on the same day the implant or IUS is removed.
Mirena may be inserted at any time during the menstrual cycle.
Inserting Mirena after abortion or miscarriage
Mirena may be inserted immediately after a first-trimester abortion or miscarriage.
Do not insert Mirena until a minimum of 6 weeks after second trimester abortion or miscarriage, or until the uterus is fully involuted. If involution is delayed, wait until involution is complete before insertion [see Warnings and Precautions (5.6, 5.7)].
If the woman has not yet had a period, consider the possibility of ovulation and conception occurring prior to insertion of Mirena. [See Contraindications (4), Warnings and Precautions (5.2), and FDA-Approved Patient Labeling.] Mirena can be inserted any time the provider can be reasonably certain the woman is not pregnant.
If Mirena is not inserted during the first 7 days of the menstrual cycle, a back-up method of contraception should be used or the patient should abstain from vaginal intercourse for 7 days to prevent pregnancy.
Inserting Mirena after Childbirth
Do not insert Mirena until a minimum of 6 weeks after delivery, or until the uterus is fully involuted. If involution is delayed, wait until involution is complete before insertion [see Warnings and Precautions (5.6, 5.7)].
If the woman has not yet had a period, consider the possibility of ovulation and conception occurring prior to insertion of Mirena. [See Contraindications (4), Warnings and Precautions (5.2)]. Mirena can be inserted any time the provider can be reasonably certain the woman is not pregnant.
If Mirena is not inserted during the first 7 days of the menstrual cycle, a back-up method of contraception should be used or the patient should abstain from vaginal intercourse for 7 days to prevent pregnancy.
There is an increased risk of perforation in lactating women. [See Warnings and Precautions (5.6).]
Tools for Insertion
- Sterile uterine sound
- Sterile tenaculum
- Antiseptic solution, applicator
Preparation for insertion
- Exclude pregnancy and confirm that there are no other contraindications to the use of Mirena.
- Gently insert a speculum to visualize the cervix.
- Thoroughly cleanse the cervix and vagina with a suitable antiseptic solution.
- Prepare to sound the uterine cavity. Grasp the upper lip of the cervix with a tenaculum forceps and gently apply traction to stabilize and align the cervical canal with the uterine cavity. Perform a paracervical block if needed. If the uterus is retroverted, it may be more appropriate to grasp the lower lip of the cervix. The tenaculum should remain in position and gentle traction on the cervix should be maintained throughout the insertion procedure.
- Gently insert a uterine sound to check the patency of the cervix, measure the depth of the uterine cavity in centimeters, confirm cavity direction, and detect the presence of any uterine anomaly. If you encounter difficulty or cervical stenosis, use dilatation, and not force, to overcome resistance. If cervical dilatation is required, consider using a paracervical block.
- The uterus should sound to a depth of 6 to 10 cm. Insertion of Mirena into a uterine cavity less than 6 cm by sounding may increase the incidence of expulsion, bleeding, pain, perforation, and possibly pregnancy.
Proceed with insertion only after completing the above steps and ascertaining that the patient is appropriate for Mirena. Ensure use of aseptic technique throughout the entire procedure.
Step 1–Opening of the package
- Open the package (Figure 1). The contents of the package are sterile.
- Using sterile gloves lift the handle of the sterile inserter and remove from the sterile package.
Step 2–Load Mirena into the insertion tube
- Push the slider forward as far as possible in the direction of the arrow thereby moving the insertion tube over the Mirena T-body to load Mirena into the insertion tube (Figure 2). The tips of the arms will meet to form a rounded end that extends slightly beyond the insertion tube.
- Maintain forward pressure with your thumb or forefinger on the slider. DO NOT move the slider downward at this time as this may prematurely release the threads of Mirena. Once the slider is moved below the mark, Mirena cannot be re-loaded.
Step 3–Setting the flange
- Holding the slider in this forward position, set the upper edge of the flange to correspond to the uterine depth (in centimeters) measured during sounding (Figure 3).
Step 4–Mirena is now ready to be inserted
- Continue holding the slider in this forward position. Advance the inserter through the cervix until the flange is approximately 1.5–2 cm from the cervix and then pause (Figure 4).
Do not force the inserter. If necessary, dilate the cervical canal.
Step 5–Open the arms
While holding the inserter steady, move the slider down to the mark to release the arms of Mirena (Figure 5). Wait 10 seconds for the horizontal arms to open completely.
Step 6–Advance to fundal position
- Advance the inserter gently towards the fundus of the uterus until the flange touches the cervix. If you encounter fundal resistance do not continue to advance. Mirena is now in the fundal position (Figure 6). Fundal positioning of Mirena is important to prevent expulsion.
Step 7–Release Mirena and withdraw the inserter
- Holding the entire inserter firmly in place, release Mirena by moving the slider all the way down (Figure 7).
- Continue to hold the slider all the way down while you slowly and gently withdraw the inserter from the uterus.
- Using a sharp, curved scissor, cut the threads perpendicular, leaving about 3 cm visible outside of the cervix [cutting threads at an angle may leave sharp ends (Figure 8)]. Do not apply tension or pull on the threads when cutting to prevent displacing Mirena.
Mirena insertion is now complete. Prescribe analgesics, if indicated. Record the Mirena lot number in the patient records.
Important information to consider during or after insertion
- If you suspect that Mirena is not in the correct position, check placement (for example, using transvaginal ultrasound). Remove Mirena if it is not positioned completely within the uterus. A removed Mirena must not be re-inserted.
If there is clinical concern, exceptional pain or bleeding during or after insertion, appropriate steps (such as physical examination and ultrasound) should be taken immediately to exclude perforation.
2.3 Patient Follow-up
Reexamine and evaluate patients 4 to 6 weeks after insertion and once a year thereafter, or more frequently if clinically indicated.
2.4 Removal of Mirena
Timing of Removal
- For contraception, remove Mirena by the end of the sixth year and replace at the time of removal with a new Mirena if continued use is desired. Replace Mirena by the end of the fifth year if continued treatment of heavy menstrual bleeding is needed.
- If pregnancy is not desired, remove Mirena during menstruation, provided the woman is still experiencing regular menses. If removal will occur at other times during the cycle, consider starting a new contraceptive method a week prior to removal. If removal occurs at other times during the cycle and the woman has had intercourse in the week prior to removal, she is at risk of pregnancy. [See Dosage and Administration (2.5).]
- Remove Mirena by applying gentle traction on the threads with forceps. (Figure 9).
- If the threads are not visible, determine location of Mirena by ultrasound [see Warnings and Precautions (5.10)].
- If Mirena is found to be in the uterine cavity on ultrasound exam, 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, examine the system to ensure that it is intact.
Removal may be associated with some pain and/or bleeding or vasovagal reactions (for example, syncope, or a seizure in an epileptic patient).
2.5 Continuation of Contraception after Removal
- If pregnancy is not desired and if a woman wishes to continue using Mirena, a new system can be inserted immediately after removal any time during the cycle.
- If a patient with regular cycles wants to start a different birth control method, time removal and initiation of new method to ensure continuous contraception. Either remove Mirena during the first 7 days of the menstrual cycle and start the new method immediately thereafter or start the new method at least 7 days prior to removing Mirena if removal is to occur at other times during the cycle.
If a patient with irregular cycles or amenorrhea wants to start a different birth control method, start the new method at least 7 days before removal.
- 3 DOSAGE FORMS AND STRENGTHS
The use of Mirena is contraindicated when one or more of the following conditions exist:
- Pregnancy or suspicion of pregnancy; cannot be used for post-coital contraception [see Warnings and Precautions (5.2)]
- Congenital or acquired uterine anomaly including fibroids if they distort the uterine cavity
- Acute pelvic inflammatory disease or a history of pelvic inflammatory disease unless there has been a subsequent intrauterine pregnancy [see Warnings and Precautions (5.4)]
- Postpartum endometritis or infected abortion in the past 3 months
- Known or suspected uterine or cervical malignancy
- Known or suspected breast cancer or other progestin-sensitive cancer, now or in the past
- Uterine bleeding of unknown etiology
- Untreated acute cervicitis or vaginitis, including bacterial vaginosis or other lower genital tract infections until infection is controlled
- Acute liver disease or liver tumor (benign or malignant)
- Conditions associated with increased susceptibility to pelvic infections [see Warnings and Precautions (5.4)]
- A previously inserted intrauterine device (IUD) that has not been removed
- Hypersensitivity to any component of this product [see Adverse Reactions (6.2)]
5 WARNINGS AND PRECAUTIONS
5.1 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.
5.2 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.
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, 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.
Long-term effects and congenital anomalies
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.
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.
5.4 Pelvic Infection
Pelvic Inflammatory Disease (PID)
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).
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.1
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.
5.5 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 (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.
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. Consider further diagnostic imaging, such as x-ray, if expulsion is suspected based on ultrasound [see Warnings and Precautions (5.10)]. 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..
5.8 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.
5.9 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.
5.10 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:
- Coagulopathy or use of 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
In addition, consider removing Mirena if any of the following conditions arise during use [see Contraindications (4)]:
- Uterine or cervical malignancy
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.
6 ADVERSE REACTIONS
The following serious or otherwise important adverse reactions are discussed in elsewhere in the labeling:
- Ectopic Pregnancy [see Warnings and Precautions (5.1)]
- Intrauterine Pregnancy [see Warnings and Precautions (5.2)]
- Group A Streptococcal Sepsis (GAS) [see Warnings and Precautions (5.3)]
- Pelvic Inflammatory Disease [see Warnings and Precautions (5.4)]
- Alterations of Bleeding Patterns [see Warnings and Precautions (5.5)]
- Perforation [see Warnings and Precautions (5.6)]
- Expulsion [see Warnings and Precautions (5.7)]
- Ovarian Cysts [see Warnings and Precautions (5.8)]
6.1 Clinical Trials Experience
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 in Table 2 reflect the experience with the use of Mirena in the adequate and well-controlled studies as well as in the supportive and uncontrolled studies for contraception and heavy menstrual bleeding (n=5,091). The data cover more than 12,101 women-years of exposure up to 5 years of use, mainly in the contraception studies (11,761 women-years). The frequencies of reported adverse drug reactions represent crude incidences.
The most common adverse reactions (≥10% users) are alterations of menstrual bleeding patterns [including unscheduled uterine bleeding (31.9%), decreased uterine bleeding (23.4%), increased scheduled uterine bleeding (11.9%), and female genital tract bleeding (3.5%)], abdominal/pelvic pain (22.6%), amenorrhea (18.4%), headache/migraine (16.3%), genital discharge (14.9%), and vulvovaginitis (10.5%). Adverse reactions reported in ≥ 5% of users are shown in Table 2.
Table 2: Adverse Reactions ≥ 5% Reported in Clinical Trials with Mirena
System Organ Class
% (N= 5,091)
Reproductive system and breast disorders
alteration of menstrual bleeding pattern, including:
unscheduled uterine bleeding
decreased uterine bleeding
increased scheduled uterine bleeding
female genital tract bleeding
benign ovarian cyst and associated complications
Nervous system disorders
Musculoskeletal and connective tissue disorders
Skin and subcutaneous
Other adverse reactions occurring in <5% of subjects include alopecia, (partial and complete) device expulsion, hirsutism, nausea, and PID/endometritis.
A separate study with 362 women who have used Mirena for more than 5 years showed a consistent adverse reaction profile in Year 6. By the end of Year 6 of use, amenorrhea and infrequent bleeding are experienced by 24% and 31% of users, respectively; irregular bleeding occurs in 15%, and prolonged bleeding in 2% of users.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of Mirena. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Arterial thrombotic and venous thromboembolic events, including cases of pulmonary emboli, deep vein thrombosis and stroke
- Device breakage
- Hypersensitivity (including rash, urticaria and angioedema)
- Increased blood pressure
7 DRUG INTERACTIONS
No drug-drug interaction studies have been conducted with Mirena.
Drugs or herbal products that induce or inhibit LNG metabolizing enzymes, including CYP3A4, may decrease or increase, respectively, the serum concentrations of LNG during the use of Mirena. However, the contraceptive effect of Mirena is mediated via the direct release of LNG into the uterine cavity and is unlikely to be affected by drug interactions via enzyme induction or inhibition.
8 USE IN SPECIFIC POPULATIONS
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.
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.
8.3 Females and Males of Reproductive Potential
Return to Fertility After Discontinuing Mirena
In two studies, return to fertility was investigated in a total of 229 women who desired pregnancy after study discontinuation and provided follow-up information. The probability to conceive within 12 months after removal of Mirena was approximately 80%.
8.4 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.
8.5 Geriatric Use
Mirena has not been studied in women over age 65 and is not approved for use in this population.
8.6 Hepatic Impairment
No studies were conducted to evaluate the effect of hepatic disease on the disposition of LNG released from Mirena [see Contraindications (4)].
Mirena (levonorgestrel-releasing intrauterine system) contains 52 mg of LNG, a progestin, and is intended to provide an initial release rate of approximately 20 mcg/day of LNG.
Levonorgestrel USP, (-)-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one, the active ingredient in Mirena, has a molecular weight of 312.4, a molecular formula of C21H28O2, and the following structural formula:
Mirena consists of a T-shaped polyethylene frame (T-body) with a steroid reservoir (hormone elastomer core) around the vertical stem. The reservoir consists of a white or almost white cylinder, made of a mixture of levonorgestrel and silicone (polydimethylsiloxane), containing a total of 52 mg levonorgestrel. The reservoir is covered by a semi-opaque silicone (polydimethylsiloxane) membrane. The T-body is 32 mm in both the horizontal and vertical directions. The polyethylene of the T-body is compounded with barium sulfate, which makes it radiopaque. A monofilament brown polyethylene removal thread is attached to a loop at the end of the vertical stem of the T-body. The polyethylene of the removal thread contains iron oxide as a colorant (see Figure 10).
The components of Mirena, including its packaging, are not manufactured using natural rubber latex.
Mirena is packaged sterile within an inserter. The inserter (Figure 11), which is used for insertion of Mirena into the uterine cavity, consists of a symmetric two-sided body and slider that are integrated with flange, lock, pre-bent insertion tube and plunger. The outer diameter of the insertion tube is 4.4 mm. The vertical stem of Mirena is loaded in the insertion tube at the tip of the inserter. The arms are pre-aligned in the horizontal position. The removal threads are contained within the insertion tube and handle. Once Mirena has been placed, the inserter is discarded.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The local mechanism by which continuously released LNG enhances contraceptive effectiveness of Mirena has not been conclusively demonstrated. Studies of Mirena and similar LNG IUS 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.
Mirena has mainly local progestogenic effects in the uterine cavity. The high local levels of LNG2 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.
Low doses of LNG are administered into the uterine cavity with the Mirena intrauterine delivery system. The initial release rate is approximately 20 mcg/day over the first 3 months tested (day 0 to day 90). It is reduced to approximately 18 mcg/day after 1 year, 10 mcg/day after 5 years, and 9 mcg/day after 6 years.
A stable serum concentration, without peaks and troughs, of LNG of 150–200 pg/mL occurs after the first few weeks following insertion of Mirena. LNG concentrations after long-term use of 12, 24, 60 and 72 months were 180±66 pg/mL, 192±140 pg/mL, 159±59 pg/mL, and 121±49 pg/mL respectively.
The apparent volume of distribution of LNG 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, LNG is conjugated at the 17β-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in serum. Significant amounts of conjugated and unconjugated 3α, 5β- tetrahydrolevonorgestrel are also present in serum, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. LNG 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 LNG concentrations seen in individuals using LNG–containing contraceptive products. In vitro studies have demonstrated that oxidative metabolism of LNG is catalyzed by CYP enzymes, especially CYP3A4.
About 45% of LNG and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The elimination half-life of LNG 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 [see Drug Interactions (7)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
[See Warnings and Precautions (5.9)]
14 CLINICAL STUDIES
14.1 Clinical Trials on Contraception
The safety and effectiveness of Mirena was studied in two clinical trials in Finland and Sweden. In these trials, 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 White, and over 70% of the subjects 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%).
The contraceptive efficacy of Mirena during extended use beyond 5 years was studied in the Mirena Extension Trial (NCT02985541), a multi-center, open-label, uncontrolled study conducted in the United States. The trial enrolled women 18 to 35 years of age who had been using Mirena for not less than 4.5 years and not more than 5 years at enrollment. The efficacy population consisted of 362 women using Mirena. Of these 47.2% were nulliparous. The women were predominantly White (75.4%); 14.1% of the women were Black/African American, and 2.5% were Asian; 11.3 % were Hispanic. The weight range was 38.5–163.5 kg (mean weight: 75.6 kg) and mean BMI was 27.9 kg/m2 (range: 15.4–57.7 kg/m2). The pregnancy rate calculated as the Pearl Index (PI) in women ≤ 36 years of age at the end of Year 6 was the primary efficacy endpoint. The PI was calculated based on 28-day equivalent exposure cycles; evaluable cycles excluded those in which back-up contraception was used unless a pregnancy occurred in that cycle. A total of 362 women contributed 3,722 cycles. The PI for the 6th year of use based on the 1 pregnancy that occurred during Year 6 and within 7 days after Mirena removal or expulsion was 0.35 with a 95% upper confidence limit of 1.95.
14.2 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.
1http://www.cdc.gov/std/tg2015/pid.htm. Accessed August 22, 2016.
16 HOW SUPPLIED/STORAGE AND HANDLING
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].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information)
- Sexually Transmitted Infections: Advise the patient that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).
- Risk of Ectopic Pregnancy: Advise the patient about the risks of ectopic pregnancy, including the loss of fertility. Teach her to recognize and report to her healthcare provider promptly any symptoms of ectopic pregnancy. [See Warnings and Precautions (5.1).]
- Pregnancy or Suspected Pregnancy: Advise the patient to inform her healthcare provider if she determines or suspects she is pregnant with Mirena in place. Advise women of the potential risks if pregnancy occurs with Mirena in place. If Mirena cannot be removed in a pregnant patient, advise her to report immediately any symptom that suggests complications of the pregnancy.
- Pelvic Infection: Advise the patient about the possibility of pelvic inflammatory disease (PID) and that PID can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Teach the patient to recognize and report to her healthcare provider promptly any symptoms of PID. These symptoms include development of menstrual disorders (prolonged or heavy bleeding), unusual vaginal discharge, abdominal or pelvic pain or tenderness, dyspareunia, chills, and fever. [See Warnings and Precautions (5.4).]
- Irregular Bleeding and Amenorrhea: Advise 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. [See Warnings and Precautions (5.5).]
- Perforation and Expulsion: Advise the patient that the IUS may be expelled from or perforate the uterus and instruct her on how she can check that the threads still protrude from the cervix. Inform her that excessive pain or vaginal bleeding during Mirena placement, worsening pain or bleeding after placement, or the inability to feel Mirena strings may occur with Mirena perforation and expulsion. Caution her not to pull on the threads and displace Mirena. Inform her that there is no contraceptive protection if Mirena is displaced or expelled. [See Warnings and Precautions (5.6, 5.7).]
- Clinical Considerations for Use and Removal: Advise the patient to contact her healthcare provider if she experiences any of the following:
- A stroke or heart attack
- 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
- Pregnancy or suspected pregnancy
- Pelvic pain or pain during sex
- HIV positive seroconversion in herself or her partner
- Possible exposure to sexually transmitted infections (STIs)
- Unusual vaginal discharge or genital sores
- Severe vaginal bleeding or bleeding that lasts a long time, or if she misses a menstrual period
- Inability to feel Mirena's threads
PATIENT PACKAGE INSERT
- This Patient Information has been approved by the U.S. Food and Drug Administration. 8/2020
PRINCIPAL DISPLAY PANEL
Mirena (levonorgestrel-releasing intrauterine system) Carton
1 Sterile Unit
NEW contains updated single-handed inserter with no removable threads
IMPORTANT: To be inserted in the uterus by a trained healthcare provider. Mirena cannot be reloaded.. See physician insert for detailed instructions for use.
(levonorgestrel-releasing intrauterine system)
— 52 mg levonorgestrel
— 1 sterile unit
— intrauterine use
INGREDIENTS AND APPEARANCE
levonorgestrel intrauterine device
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50419-423 Route of Administration INTRAUTERINE Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEVONORGESTREL (UNII: 5W7SIA7YZW) (LEVONORGESTREL - UNII:5W7SIA7YZW) LEVONORGESTREL 52 mg Inactive Ingredients Ingredient Name Strength DIMETHICONE (UNII: 92RU3N3Y1O) BARIUM SULFATE (UNII: 25BB7EKE2E) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50419-423-01 1 in 1 CARTON; Type 4: Device Coated/Impregnated/Otherwise Combined with Drug 05/30/2014 2 NDC:50419-423-08 1 in 1 CARTON; Type 4: Device Coated/Impregnated/Otherwise Combined with Drug 12/08/2016 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021225 10/01/2009 Labeler - Bayer HealthCare Pharmaceuticals Inc. (005436809) Establishment Name Address ID/FEI Business Operations Bayer Schering Pharma Oy 369758383 MANUFACTURE(50419-423)