warnings and cautions
5 WARNINGS AND PRECAUTIONS • Remove Kyleena if pregnancy occurs with Kyleena 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 following insertion of LNG IUS; strict aseptic technique is essential during insertion. ( 5.3 ) • Before using Kyleena, consider the risks of PID. ( 5.4 ) • Uterine perforation may occur and may reduce contraceptive effectiveness or require surgery. Risk is increased if inserted in lactating women and may be increased if inserted in women with fixed retroverted uteri and postpartum. ( 5.5 ) • Partial or complete expulsion may occur, which can be unnoticed, leading to loss of contraceptive efficacy. ( 5.6 ) • Evaluate persistent enlarged ovarian follicles or ovarian cysts. ( 5.7 ) • Bleeding patterns become altered, may remain irregular and amenorrhea may ensue. ( 5.8 ) • Kyleena can be safely scanned with MRI only under certain conditions. ( 5.11 ) 5.1 Risk of Ectopic Pregnancy Evaluate women for ectopic pregnancy if they become pregnant with Kyleena in place because the likelihood of a pregnancy being ectopic is increased with Kyleena. Approximately one-half of pregnancies that occur with Kyleena 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 if an amenorrheic woman starts bleeding. The incidence of ectopic pregnancy in clinical trials with Kyleena, which excluded women with a history of ectopic pregnancy, was approximately 0.2% per year. The risk of ectopic pregnancy in women who have a history of ectopic pregnancy and use Kyleena 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 Risks with Intrauterine Pregnancy If pregnancy occurs while using Kyleena, remove Kyleena because leaving it in place may increase the risk of spontaneous abortion and preterm labor. Removal of Kyleena or probing of the uterus may also result in spontaneous abortion. In the event of an intrauterine pregnancy with Kyleena, consider the following: Septic abortion In patients becoming pregnant with an IUS in place, septic abortion—with septicemia, septic shock, and death—may occur. Continuation of pregnancy If a woman becomes pregnant with Kyleena in place and if Kyleena cannot be removed or the woman chooses not to have it removed, warn her that failure to remove Kyleena increases the risk of miscarriage, sepsis, premature labor and premature delivery. Advise her of isolated reports of virilization of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place [see Use in Specific Populations ( 8.1 )] . Follow her pregnancy closely and advise her to report immediately any 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 a LNG-releasing IUS. 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 Kyleena is essential in order to minimize serious infections such as GAS. 5.4 Pelvic Infection Promptly examine users with complaints of lower abdominal or pelvic pain, odorous discharge, unexplained bleeding, fever, genital lesions or sores. Remove Kyleena in cases of recurrent endometritis or pelvic inflammatory disease, or if an acute pelvic infection is severe or does not respond to treatment. Pelvic Inflammatory Disease (PID) Kyleena 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, PID was observed in 0.5% of women overall and occurred more frequently within the first year and most often within the first month after insertion of Kyleena. Women at increased risk for PID PID is often associated with a sexually transmitted infection (STI), and Kyleena does not protect against STI. 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], intravenous drug abuse). Subclinical 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 Kyleena after initiation of antibiotic therapy is usually appropriate. 1 Actinomycosis Actinomycosis has been associated with IUDs. Remove Kyleena from symptomatic women and treat with 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 Kyleena removal and treatment. When possible, confirm a Pap smear diagnosis with cultures. 5.5 Perforation Perforation (total or partial, including penetration/embedment of Kyleena in the uterine wall or cervix) may occur most often during insertion, although the perforation may not be detected until sometime later. The incidence of perforation during clinical trials was < 0.1%. The risk of uterine perforation is increased in women who have recently given birth, and in women who are breastfeeding at the time of insertion. In a large postmarketing safety study conducted in the US, the risk of uterine perforation was highest when insertion occurred within ≤ 6 weeks postpartum, and also higher with breastfeeding at the time of insertion [see Adverse Reactions ( 6.2 )]. The risk of perforation may be increased if Kyleena is inserted when the uterus is fixed, retroverted or not completely involuted. If perforation occurs, locate and remove Kyleena. Surgery may be required. Delayed detection or removal of Kyleena 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 addition, perforation may reduce contraceptive efficacy and result in pregnancy. 5.6 Expulsion Partial or complete expulsion of Kyleena may occur resulting in the loss of efficacy. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. Kyleena 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 )]. In clinical trials, a 5-year expulsion rate of 3.5% (59 out of 1,690 subjects) was reported. The risk of expulsion is increased with insertions immediately after delivery and appears to be increased with insertion after second-trimester abortion based on limited data. In a large postmarketing safety study conducted in the US, the risk of expulsion was lower with breastfeeding status [see Adverse Reactions ( 6.2 )]. Remove a partially expelled Kyleena. If expulsion has occurred, a new Kyleena can be inserted any time the provider can be reasonably certain the woman is not pregnant. 5.7 Ovarian Cysts Because the contraceptive effect of Kyleena is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age using Kyleena. Ovarian cysts (reported as adverse reactions if they were abnormal, non-functional cysts and/or had a diameter >3 cm on ultrasound examination) were reported at least once over the course of clinical trials in 22% of women using Kyleena, and 0.6% of subjects discontinued because of an ovarian cyst. Most ovarian 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. 5.8 Bleeding Pattern Alterations Kyleena can alter the bleeding pattern and result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea. During the first 3–6 months of Kyleena use, the number of bleeding and spotting days may be higher and bleeding patterns may be irregular. Thereafter, the number of bleeding and spotting days usually decreases but bleeding may remain irregular. In Kyleena clinical trials, amenorrhea developed by the end of the first year of use in approximately 12% of Kyleena users. A total of 81 subjects out of 1,697 (4.8%) discontinued due to uterine bleeding complaints. Table 2 shows the bleeding patterns as documented in the Kyleena clinical trials based on 90-day reference periods. Table 3 shows the number of bleeding and spotting days based on 28-day cycle equivalents. Table 2: Bleeding Patterns Reported with Kyleena in Contraception Studies (by 90-day reference periods) Kyleena First 90 days N=1,566 Second 90 days N=1,511 End of year 1 N=1,371 End of year 3 N=975 End of year 5 N=530 Amenorrhea 1 <1% 5% 12% 20% 23% Infrequent bleeding 2 10% 20% 26% 26% 26% Frequent bleeding 3 25% 10% 4% 2% 2% Prolonged bleeding 4 57% 14% 6% 2% 1% Irregular bleeding 5 43% 25% 17% 10% 9% 1 Defined as subjects with no bleeding/spotting throughout the 90-day reference period 2 Defined as subjects with 1 or 2 bleeding/spotting episodes in the 90-day reference period 3 Defined as subjects with more than 5 bleeding/spotting episodes in the 90-day reference period 4 Defined as subjects with bleeding/spotting episodes lasting more than 14 days in the 90-day reference period. Subjects with prolonged bleeding may also be included in one of the other categories (excluding amenorrhea) 5 Defined as subjects with 3 to 5 bleeding/spotting episodes and less than 3 bleeding/spotting-free intervals of 14 or more days Table 3: Mean number of Bleeding and Spotting Days per 28-day Cycle Equivalent 28-day Cycle Equivalent Cycle 1 N=1,619 Cycle 4 N=1,575 Cycle 7 N=1,518 Cycle 13 N=1,394 Cycle 39 N=913 Cycle 65 N=322 Days on treatment 1–28 85–112 169–196 337–364 1065–1092 1793-1820 Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Number of bleeding days 7.2 (5.9) 3.2 (3.6) 2.2 (3.0) 1.5 (2.4) 1.0 (2.0) 0.9 (1.8) Number of spotting days 8.6 (6.0) 4.6 (4.4) 3.5 (3.4) 2.9 (3.0) 2.2 (2.6) 2.1 (2.4) If a significant change in bleeding develops during prolonged use, take appropriate diagnostic measures to rule out endometrial pathology . Consider the possibility of pregnancy if menstruation does not occur within six weeks of the onset of a 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. 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 Kyleena, because some breast cancers are hormone-sensitive [see Contraindications ( 4 )] . Spontaneous reports of breast cancer have been received during postmarketing experience with a LNG-releasing IUS. 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 Kyleena 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 Kyleena if any of the following conditions arise during use: • 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 ( 5.5 , 5.6 )]. Exclude pregnancy and verify the location of Kyleena, for example, by sonography, X-ray, or by gentle exploration of the cervical canal with a suitable instrument. If Kyleena is displaced, remove it. A new Kyleena may be inserted at that time or during the next menses if it is certain that conception has not occurred. If Kyleena is in place with no evidence of perforation, no intervention is indicated. 5.11 Magnetic Resonance Imaging (MRI) Safety Information Non-clinical testing has demonstrated that Kyleena is MR Conditional. A patient with Kyleena can be safely scanned in an MR system meeting the following conditions: • Static magnetic field of 3.0 T or less • Maximum spatial field gradient of 36,000 gauss/cm (360 T/m) • Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 4W/kg (First Level Controlled Operating Mode) Under the scan conditions defined above, the Kyleena IUS is expected to produce a maximum temperature rise of less than 2°C after 15 minutes of continuous scanning. In non-clinical testing, the image artifact caused by the IUS extended up to 5 mm from the IUS when imaged with a gradient echo pulse sequence and a 3.0 T MRI system. MRI