Mirena

• • 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

• • Insert Mirena into the uterine cavity during the first seven days of the menstrual cycle or immediately after a first trimester abortion. Back up contraception is not needed when Mirena is inserted as directed.
• • Postpone postpartum insertion and insertions following second trimester abortions a minimum of six weeks 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)] .

Tools for Insertion

Preparation

• • Gloves
• • Speculum
• • Sterile uterine sound
• • Sterile tenaculum
• • Antiseptic solution, applicator

Procedure

• • Sterile gloves
• • Mirena with inserter in sealed package
• • Instruments and anesthesia for paracervical block, if anticipated
• • Consider having an unopened backup Mirena available
• • Sterile, sharp curved scissors

Preparation for insertion

• • Exclude pregnancy and confirm that there are no other contraindications to the use of Mirena.
• • Ensure that the patient understands the contents of the Patient Information Booklet and obtain the signed patient informed consent located on the last page of the Patient Information Booklet. With the patient comfortably in lithotomy position, do a bimanual exam to establish the size, shape and position of the uterus.
• • 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.

Insertion Procedure

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 gloveslift the handle of the sterile inserter and remove from the sterile package.

• • 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.

• • 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.

s

• • 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. Keep a copy of the Consent Form with lot number for your records.

• • 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.

• • Reexamine and evaluate patients 4 to 6 weeks after insertion and once a year thereafter, or more frequently if clinically indicated.

2.3 Removal of Mirena

• • Mirena should not remain in the uterus after 5 years.
• • If pregnancy is not desired, the removal should be carried out 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 (2.4 ).]

Preparation

• •Gloves
• •Speculum

Procedure

• •Sterile forceps

Removal Procedure

• • 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).

• • 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

Mirena is a LNG-releasing IUS consisting of a T-shaped polyethylene frame with a steroid reservoir containing a total of 52 mg LNG.

4 CONTRAINDICATIONS

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 neoplasia
• •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.

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.

5.3 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.

5.4 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.

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)].

5.6 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.

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 if Mirena is inserted when the uterus is fixed retroverted or not completely involuted during the postpartum period. Delay Mirena insertion a minimum of six weeks or until involution is complete following a delivery or a second trimester abortion.

5.7 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, Mirena may be replaced within 7 days after the onset of a menstrual period after pregnancy has been ruled out.

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. Two observational studies have not provided evidence of an increased risk of breast cancer during the use of Mirena.

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
• •Jaundice

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. IfMirenais 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 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 LNG IUS (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 two 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.

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.

• •Angioedema
• •Device breakage

7 DRUG INTERACTIONS

No drug-drug interaction studies have been conducted with Mirena.

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 LNG include:

• •Barbiturates
• •Bosentan
• •Carbamazepine
• •Efavirenz
• •Felbamate
• •Griseofulvin
• •Nevirapine
• •Oxcarbazepine
• •Phenytoin
• •Rifabutin
• •Rifampin
• •St. John’s 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. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels.

Consult the labeling of all concurrently used drugs to obtain further information about interactions with Mirena or the potential for enzyme alterations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

The use of Mirena during an existing or suspected pregnancy is contraindicated. 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. [See Contraindications ( 4) and Warnings and Precautions (5.1, 5.2).]

8.3 Nursing Mothers

In general, no adverse effects of progestin-only contraceptives have been found on breastfeeding performance or on the health, growth, or development of the infant. Isolated postmarketing cases of decreased milk production have been reported. Small amounts of progestins were observed to pass into the breast milk of nursing mothers who used Mirena, resulting in detectable steroid levels in infant serum. [See Warnings and Precautions ( 5.6).]

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)].

8.7 Renal Impairment

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

11 DESCRIPTION

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: