LEVONORGESTREL Drug Interactions: What You Need to Know
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Drug Interactions (FDA Label)
INTERACTIONS No drug-drug interaction studies have been conducted with Kyleena. 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 Kyleena. However, the contraceptive effect of Kyleena 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.
Contraindications
LILETTA is contraindicated when one or more of the following conditions exist: Pregnancy [see Use in Specific Populations ( 8.1 ) ] For use as post-coital contraception (emergency contraception) Congenital or acquired uterine anomaly, including leiomyomas, that distorts the uterine cavity and would be incompatible with correct IUS placement [see Warnings and Precautions ( 5.10 )] Acute pelvic inflammatory disease (PID) [see Warnings and Precautions ( 5.4 )] Postpartum endometritis or infected abortion in the past 3 months [see Warnings and Precautions ( 5.2 , 5.4 )] Known or suspected uterine or cervical malignancy Known or suspected breast cancer or other hormone-sensitive cancer, now or in the past [see Warnings and Precautions ( 5.9 )] Uterine bleeding of unknown etiology [see Warnings and Precautions ( 5.10 )] Untreated acute cervicitis or vaginitis, including bacterial vaginosis, known chlamydial or gonococcal cervical infection, or other lower genital tract infections until infection is controlled [see Warnings and Precautions ( 5.4 )] 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 IUS that has not been removed A history of hypersensitivity reaction to any component of LILETTA. Reactions may include rash, urticaria, and angioedema [see Adverse Reactions ( 6.2 )] . Pregnancy ( 4 ) Use for post-coital contraception (emergency contraception) ( 4 ) Congenital or acquired uterine anomaly that distorts the uterine cavity and would be incompatible with correct IUS placement ( 4 ) Acute pelvic inflammatory disease (PID) ( 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 hormone-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 infections ( 4 ) A previously inserted IUS that has not been removed ( 4 ) Hypersensitivity to any component of LILETTA ( 4 )
Related 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 or require surgery. Risk is increased if inserted in patients who have fixed retroverted uteri, are postpartum, or are lactating. ( 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 patients for ectopic pregnancy if they become pregnant with LILETTA in place because the likelihood of a pregnancy being ectopic is increased with use of an IUS. Approximately half of pregnancies that occur with an IUS 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 patient. If an ectopic pregnancy is confirmed, LILETTA should be removed. The incidence of ectopic pregnancy in the clinical study on contraception with LILETTA, which excluded participants with a history of ectopic pregnancy who did not have a subsequent intrauterine pregnancy, was approximately 0.12 per 100 women-years. There were no ectopic pregnancies in the clinical study on heavy menstrual bleeding with LILETTA. The risk of ectopic pregnancy in patients who have a history of ectopic pregnancy and use LILETTA is unknown. Patients 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. Patients 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., 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 patient 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 had an infected abortion in the prior 3 months. Continuation of P regnancy If a patient becomes pregnant with LILETTA in place and if LILETTA cannot be removed or the patient chooses not to have it removed, warn the patient 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 instructions to immediately report 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 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. 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. Patients 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. In the clinical study on contraception with LILETTA, pelvic infection was diagnosed in 0.8% of participants. Pelvic infection was diagnosed as PID in 0.5% of participants and as endometritis in 0.3% of participants. Infections occurred following variable duration-of-use. One participant diagnosed with PID and two participants 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. In the clinical study on heavy menstrual bleeding with LILETTA, there was one participant diagnosed with PID approximately 5 months after LILETTA insertion. Patients at Increased Risk for PID or Endometritis 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 patients who have multiple sexual partners, and for patients whose sexual partner(s) have multiple sexual partners. Patients who have had PID or endometritis are at increased risk for recurrence or re-infection. Other risk factors for these infections include unprotected sex and acquired immune deficiency syndrome (AIDS). Asymptomatic PID or Endometritis PID or endometritis may be asymptomatic but still result in tubal damage and its sequelae. Treatment of PID or Endometritis In IUS users with suspected or diagnosed PID or endometritis, obtain microbial specimens, including those for sexually transmitted infections, and initiate antibiotic treatment promptly. After initiation of antibiotic treatment, the IUS may be removed or kept in place. The patient should continue to receive antibiotic treatment according to current recommendations and should have close clinical follow-up. Guidelines for PID or endometritis treatment are available from the Centers for Disease Control (CDC), Atlanta, Georgia. 1 If the patient opts for discontinuing IUS use, remove LILETTA after initiation of antibiotic treatment to avoid the potential risk for bacterial spread resulting from the removal procedure. If the patient opts for ongoing IUS contraception, the patient may forego immediate removal of LILETTA after initiation of antibiotic treatment. However, the patient should have close clinical follow-up. If no clinical improvement occurs within 48–72 hours of initiating treatment, IUS removal is appropriate with continued antibiotic therapy, as indicated. In the LILETTA clinical study on contraception, 12 of the 14 participants who developed PID or endometritis were successfully treated without removal of LILETTA (one of the 14 participants developed PID 30 days after removal).
Actinomycosis
Actinomycosis has been associated with IUS use. Symptomatic patients with known actinomycosis infection should have LILETTA removed and receive antibiotics. Actinomycetes can be found in the genital tract cultures in healthy patients 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 risk of perforation may be increased if an IUS 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. 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 participants, compared to 1.0 per 1,000 insertions for non-lactating participants. The incidence of perforation during or following LILETTA insertion in the clinical studies, which excluded breastfeeding participants, was 0.1%.
5.6 Expulsion Partial or complete expulsion of LILETTA may occur, resulting in the loss of contraceptive protection. In the clinical study on contraception with LILETTA, an overall expulsion rate of 4.1% over 8 years was reported, with a rate of 2.4% in nulliparous participants and 6.4% in parous participants. The majority (70.4%) occur in the first 12 months, with 23.9% occurring in the first three months and 42.3% in the first six months, cumulatively. Risk of expulsion is increased for patients with a history of heavy menstrual bleeding or greater than normal BMI at the time of insertion. In the clinical study on heavy menstrual bleeding with LILETTA, 8.6% of participants experienced expulsions, with two-thirds occurring within the first 90 days.
About
90% of the expulsions occurred in overweight or obese participants. 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 is increased with insertions performed immediately after delivery; it appears to be increased with insertions performed after second-trimester abortion, based on limited data. Remove a partially expelled LILETTA. If expulsion has occurred, a new LILETTA may be inserted when there is reasonable certainty the patient is not pregnant.
5.7 Ovarian Cysts The contraceptive effect of LILETTA is mainly due to its local effects within the uterus; therefore, ovulatory cycles with follicular rupture usually occur in patients of fertile age using LILETTA. 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. In the clinical study on contraception, symptomatic ovarian cysts occurred in 4.7% of participants using LILETTA over the course of 8 years, and 0.3% of participants discontinued use of LILETTA because of an ovarian cyst. In the clinical study on heavy menstrual bleeding, symptomatic ovarian cysts occurred in 1.0% of participants using LILETTA over the course of 6 months. Evaluate persistent ovarian cysts. Surgical intervention is not usually required, but may be necessary in some cases, and occurred in 1 (0.06%) of participants in the LILETTA study. Discuss this risk with patients, as indicated.
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.
Contraception Study
The amenorrhea rates observed in the LILETTA clinical study on contraception are shown in Table 2. The bleeding and spotting days, based on 28-day cycle equivalents, are shown in Table 3. In this study, 2.5% of participants discontinued LILETTA due to bleeding complaints.
Table
2: Amenorrhea Rates Last 90-Day Interval of Year Year 1 2 3 4 5 6 7 8 Amenorrhea Rate* 19% 27% 37% 37% 40% 40% 39% 39% *Amenorrhea is defined as no bleeding and/or spotting.
Table
3: Bleeding and Spotting Days per 28-Day Cycle Equivalent 28- D ay Cycle Equivalent N* Cycle 1 N=1,691 Cycle 4 N=1,5 93 Cycle 7 N=1, 519 Cycle 13 N= 1,395 Cycle 26 N= 1,109 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 *N includes all LILETTA participants in the clinical study on contraception.
Heavy Menstrual Bleeding Study
The amenorrhea rates observed in the LILETTA clinical study on heavy menstrual bleeding (HMB) are shown in Table 4. Amenorrhea developed in 19% of LILETTA study participants by Cycle 6.
Table
4: Amenorrhea Rates for 28-Day Treatment Cycles 28-Day Cycle N Baseline N=87 Cycle 1 N=87 Cycle 2 N=88 Cycle 3 N=88 Cycle 4 N=82 Cycle 5 N=82 Cycle 6 N=79 Amenorrhea Rate* 0% 3% 8% 11% 13% 17% 19% *Amenorrhea is defined as no bleeding and/or spotting. Percentages within each cycle are based on the number of participants who completed the cycle. The bleeding and spotting days, based on 28-day cycle equivalents, are shown in Table 5. In this study, 3.8% of LILETTA participants discontinued due to bleeding complaints.
Table
5: Bleeding and Spotting Days from Baseline to Treatment Cycle 3 and Cycle 6 28-Day Cycle N* Baseline N=87 Cycle 3 N=88 Cycle 6 N=79 Mean SD Mean SD Mean SD Number of Bleeding Days 4.9 1.5 3.7 3.8 2.2
3.5 Number of Spotting Days 1.8 1.1 7.3 7.0 5.1 5.8 *N includes participants with at least one complete 28-day cycle of product-use. Calculations are based on complete 28-day cycles (at least 23 days in length). Resumption of Menses After Discontinuation In the LILETTA clinical study on contraception, 651 of 652 (99.8%) participants 16-35 years of age at enrollment that were evaluated resumed menses after LILETTA removal. This excludes twelve participants (9 became pregnant, 2 had a hysterectomy, and 1 had ovulatory dysfunction).
Other Bleeding Pattern
Changes If a significant change in bleeding develops during prolonged use, conduct diagnostic tests to assess possible endometrial pathology. Consider the possibility of pregnancy, including ectopic 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 patients unless indicated by other signs of pregnancy or pelvic pain.