warnings and cautions
5 WARNINGS AND PRECAUTIONS Remove LILETTA if pregnancy occurs with LILETTA in place and LILETTA is in the uterus. 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 ) Severe infection or sepsis, including Group A streptococcal sepsis (GAS), have been reported following insertion of LNG-releasing IUSs; strict aseptic technique is essential during insertion. ( 5.3 ) Before using LILETTA, consider the risks of pelvic infection. ( 5.4 ) Perforation may occur and reduce contraceptive effectiveness. Risk is increased if inserted in women with fixed retroverted uteri, during lactation, or postpartum. ( 5.5 ) Partial or complete expulsion may occur. ( 5.6 ) Evaluate persistent enlarged ovarian follicles or ovarian cysts. ( 5.7 ) Bleeding patterns can become altered, may remain irregular and amenorrhea may ensue. ( 5.8 ) 5.1 Ectopic Pregnancy Evaluate women for ectopic pregnancy if they become pregnant with LILETTA in place because the likelihood of a pregnancy being ectopic is increased with LILETTA. Approximately half of pregnancies that occur with LILETTA 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 menses or new onset bleeding in an amenorrheic woman. If an ectopic pregnancy is confirmed, LILETTA should be removed. The incidence of ectopic pregnancy in the clinical trial with LILETTA, which excluded women with a history of ectopic pregnancy who did not have a subsequent intrauterine pregnancy, was approximately 0.12 per 100 women-years. The risk of ectopic pregnancy in women who have a history of ectopic pregnancy and use LILETTA is unknown. Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection have a higher risk of ectopic pregnancy. Ectopic pregnancy may require surgery and may result in loss of fertility. Women who use LILETTA should be informed about recognizing the signs and symptoms of ectopic pregnancy and promptly reporting them to their healthcare professional, and about the associated risks of ectopic pregnancy (e.g., the loss of fertility). 5.2 Intrauterine Pregnancy If pregnancy occurs while using LILETTA, determine if LILETTA is in the uterus. If LILETTA is in the uterus, attempt to remove LILETTA because leaving it in place may increase the risk of spontaneous abortion and preterm labor. Removal of LILETTA or probing of the uterus may also result in spontaneous abortion. In the event of an intrauterine pregnancy with LILETTA, consider the following: Septic A bortion If a woman becomes pregnant with an IUS in place, septic abortion potentially including septicemia, septic shock, and death may occur. Septic abortion typically requires hospitalization and treatment with intravenous antibiotics. Septic abortion may result in spontaneous abortion or a medical indication for pregnancy termination. Should severe infection of the uterus occur, hysterectomy may be required, which will result in permanent infertility. LILETTA is contraindicated in patients who have has an infected abortion in the prior 3 months. Continuation of P regnancy If a woman becomes pregnant with LILETTA in place and if LILETTA cannot be removed or the woman chooses not to have it removed, warn her that failure to remove LILETTA increases the risk of miscarriage, sepsis, premature labor, and premature delivery. Prenatal care should include counseling about these risks and that she should report immediately any flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge or leakage of fluid, or any other symptom that suggests complications of the pregnancy. 5.3 Sepsis Severe infection or sepsis, including Group A streptococcal sepsis (GAS), have been reported following insertion of LNG-releasing IUSs. 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 LILETTA is essential in order to minimize serious infections such as GAS. 5.4 Pelvic Inflammatory Disease or Endometritis Insertion of LILETTA is contraindicated in the presence of known or suspected PID or endometritis or a history of PID unless there has been a subsequent intrauterine pregnancy. As well, it is contraindicated in patients with untreated acute cervicitis or vaginitis (including bacterial vaginosis), known chlamydial or gonococcal cervical infection, or other known lower genital tract infections, until the infection is controlled. IUSs have been associated with an increased risk of PID, most likely due to organisms being introduced into the uterus during insertion. Assess risk factors for infection accordingly. In the clinical trial with LILETTA, pelvic infection was diagnosed in 0.8% of women. Pelvic infection was diagnosed as PID in 0.5% of women and as endometritis in 0.3% of women. Infections occurred following variable duration of use. One woman diagnosed with PID and two women diagnosed with endometritis developed the infection within a week of LILETTA insertion. One case of endometritis was diagnosed at 39 days after LILETTA insertion. The remaining 11 cases of PID and endometritis were diagnosed more than six months after insertion, including one at 30 days after IUS removal. Women who use LILETTA should be counseled to promptly notify a healthcare professional if they develop lower abdominal or pelvic pain, fever, chills, unusual or malodorous discharge, unexplained bleeding, genital lesions or sores, or dyspareunia. In such circumstances, perform a pelvic examination promptly to evaluate for possible pelvic infection. Remove LILETTA in cases of recurrent PID or endometritis, or if an acute pelvic infection is severe or does not respond to treatment. Women at I ncreased R isk for PID or E ndometritis PID and endometritis are often associated with a sexually transmitted infection (STI), and LILETTA does not protect against STIs. The risk of PID or endometritis is greater for women who have multiple sexual partners, and for women whose sexual partner(s) have multiple sexual partners. Women who have had PID or endometritis are at increased risk for a recurrence or re-infection. Other risk factors for these infections include leukemia, acquired immune deficiency syndrome (AIDS), and illicit intravenous drug use. Asymptomatic PID or E ndometritis PID or endometritis may be asymptomatic but still result in tubal damage and its sequelae. Treatment of PID or E ndometritis Following a diagnosis of PID or endometritis, or suspected PID or endometritis, perform appropriate testing for sexually transmitted infection and initiate antibiotic therapy promptly. LILETTA does not need to be removed immediately if the woman needs ongoing contraception 1 . In the LILETTA clinical trial, 12 of the 14 women who developed PID or endometritis were successfully treated without removal of LILETTA (one of the 14 women developed PID 30 days after removal). Reassess the woman in 48-72 hours. If no clinical improvement occurs, continue antibiotics and consider removal of LILETTA. If the woman wants to discontinue use, remove LILETTA after antibiotics have been started to avoid the potential risk for bacterial spread resulting from the removal procedure. Guidelines for PID or endometritis treatment are available from the Centers for Disease Control (CDC), Atlanta, Georgia. 1 Actinomycosis Actinomycosis has been associated with IUS use. Symptomatic women with known actinomycosis infection should have LILETTA removed and receive antibiotics. Actinomycetes can be found in the genital tract cultures in healthy women without IUSs. The significance of actinomyces-like organisms on Pap test in an asymptomatic IUS user is unknown, and so this finding alone does not always require LILETTA removal and treatment. When possible, confirm a Pap test diagnosis with cultures. 5.5 Perforation Perforation (total or partial, including penetration/embedment of LILETTA in the uterine wall or cervix) may occur, most often during insertion, although the perforation may not be detected until sometime later. Perforation may also occur at any time during IUS use. Perforation may reduce contraceptive efficacy and result in pregnancy. This may be associated with severe pain and continued bleeding. The incidence of perforation during or following LILETTA insertion in the clinical trial, which excluded breastfeeding women, was 0.1%. If perforation is suspected the IUS should be removed as soon as possible, surgery may be required. Delayed detection or removal of LILETTA in case of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, abscesses, and erosion of adjacent viscera. In a large prospective comparative non-interventional cohort study with another IUS 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. The risk of perforation may be increased if LILETTA is inserted when the uterus is fixed retroverted or not completely involuted during the post-partum period. Delay LILETTA insertion a minimum of four weeks or until involution is complete following a delivery or a second trimester abortion. 5.6 Expulsion Partial or complete expulsion of LILETTA may occur, resulting in the loss of contraceptive protection. In the clinical trial with LILETTA, an overall expulsion rate of 4.0% over 6 years was reported, with a rate of 2.2% in nulliparous women and 6.2% in parous women. The majority (73.5%) occur in the first 12 months, with 25.0% occurring in the first three months and 44.1% in the first six months, cumulatively. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. LILETTA typically decreases menstrual bleeding over time; therefore, an increase in menstrual bleeding may be indicative of an expulsion. Consider further diagnostic imaging, such as sonography or X-ray, to confirm expulsion if LILETTA is not found in the uterus. The risk of expulsion may be increased when the uterus is not completely involuted at the time of insertion. Delay LILETTA insertion a minimum of 4 weeks or until uterine involution is complete following a delivery or a second trimester abortion. Remove a partially expelled LILETTA. If expulsion has occurred, a new LILETTA may be inserted within 7 days after the onset of a menstrual period after pregnancy has been ruled out. 5.7 Ovarian Cysts Because the contraceptive effect of LILETTA is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age using LILETTA. Sometimes atresia of the follicle is delayed and the follicle may continue to grow. Most ovarian cysts that occur during use of LNG-releasing IUSs are asymptomatic and disappear spontaneously during two to three months of observation. Cysts that cause clinical symptoms can result in pelvic or abdominal pain or dyspareunia. Symptomatic ovarian cysts occurred in 4.5% of subjects using LILETTA over the course of 6 years, and 0.3% of subjects discontinued use of LILETTA because of an ovarian cyst. Evaluate persistent ovarian cysts. Surgical intervention is not usually required, but may be necessary in some cases. Discuss this risk with patients who use LILETTA. 5.8 Bleeding Pattern Alterations LILETTA can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea, and amenorrhea. During the first three to six months of LILETTA use, the number of bleeding and spotting days may increase and irregular bleeding patterns may develop. Thereafter, the number of bleeding and spotting days usually decreases but bleeding may remain irregular. In the LILETTA clinical trial, amenorrhea developed in approximately 19% of LILETTA users by the end of the first year of use, 27% by the end of the second year of use, 37% by the end of the third year of use, 37% by the end of the fourth year of use, 40% by the end of the fifth year of use, and 40% by the end of the sixth year of use. In the trial, 2.3% of LILETTA subjects discontinued due to bleeding complaints. Table 2 shows the bleeding and spotting days based on 28-day cycle equivalents. Table 2: Mean Number of Bleeding and Spotting Days per 28-Day Cycle Equivalent 28- D ay Cycle Equivalent Cycle 1 N=1 , 691 Cycle 4 N=1 , 5 93 Cycle 7 N= 1,519 Cycle 13 N= 1,395 Cycle 26 N= 1,108 Days on treatment 1-28 85-112 169-196 337-364 674-728 Mean SD Mean SD Mean SD Mean SD Mean SD Number of bleeding days 5.8 5.2 2.3 3.3 1.6 2.7 1.2 2.4 0.8 1.8 Number of spotting days 9.0 5.9 4.3 4.2 3.2 3.6 2.7 3.4 1.9 2.8 Note: Includes all LILETTA subjects. In the LILETTA clinical trial, 537 of 538 (99.8%) women evaluated experienced menses after LILETTA removal. This excludes fourteen women who became pregnant (9 women), had a hysterectomy (3 women), were considered menopausal after removal (1 woman), or had ovulatory dysfunction (1 woman). If a significant change in bleeding develops during prolonged use, conduct diagnostic tests to assess possible endometrial pathology. Consider the possibility of pregnancy if menstruation does not occur within six weeks of the onset of a previous menstruation. After excluding pregnancy, repeat pregnancy tests are generally not necessary in amenorrheic women unless indicated, by other signs of pregnancy or pelvic pain. 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, including LILETTA, because some breast cancers are hormone-sensitive [ see Contraindications ( 4 ) ] . Spontaneous reports of breast cancer have been received during postmarketing experience with LNG-releasing IUSs. Observational studies have not provided consistent evidence of an increased risk of breast cancer with use of a LNG-releasing IUS. 5.10 Clinical Considerations for Use and Removal Obtain a complete medical and social history, including partner status, to determine conditions that might influence the selection of an IUS for contraception. Exclude underlying endometrial pathology (e.g. polyps or cancer) prior to the insertion of LILETTA in women with persistent or uncharacteristic bleeding because irregular bleeding/spotting is common during the first months of LILETTA use and may preclude adequate assessment after insertion. LILETTA is contraindicated in women with uterine bleeding of unknown etiology. Exclude underlying congenital or acquired uterine anomalies, including fibroids, that distort the uterine cavity and would be incompatible with correct IUS placement [see Contraindications ( 4 )] . Ensure a previously inserted IUS has been removed prior to insertion of LILETTA [see Contraindications ( 4 )] . Assess whether the woman is at increased risk of infection (e.g., leukemia, acquired immune deficiency syndrome [AIDS], IV drug abuse), or has a history of PID unless there has been a subsequent intrauterine pregnancy. LILETTA does not protect against HIV/STI transmission [see Warnings and Precautions ( 5.4 )]. Use LILETTA with caution after careful assessment if any of the following conditions exist, and consider removal of the IUS 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 or frequent headache Marked increase of blood pressure Severe arterial disease such as stroke or myocardial infarction Consider removing LILETTA 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 IUS may have been displaced, (for example, expulsed or perforated the uterus) [see Warnings and Precautions ( 5.5 , 5.6 )] . Exclude pregnancy and verify the location of LILETTA by an appropriate diagnostic method, e.g. ultrasonography, X-ray, or gentle exploration of the cervical canal with a suitable instrument [see Dosage and Administration ( 2.6 )] . If LILETTA is displaced, remove it. A new LILETTA may be inserted at that time or during the next menses if it is certain that conception has not occurred. If LILETTA is in place with no evidence of perforation, no intervention is indicated. 5 . 11 Magnetic Resonance Imaging (MRI) Information LILETTA is MR Safe. LILETTA is compatible with MRI and should not interfere with imaging.