Liletta is under study in a prospective phase 3 clinical trial aimed at extending the approved duration of this levonorgestrel 52-mg IUS.
Of women using reversible contraception in the United States, 16% use an intrauterine device (IUD) equaling 4.4 million women in 2014.1,2 Today, five IUDs are available: Paragard®, a non-hormonal copper IUD, and four hormonal intrauterine system (IUS) products containing levonorgestrel – Liletta®, Mirena®, Kyleena® and Skyla®. These systems are categorized by the amount of levonorgestrel that they contain -52, 19.5 or 13.5 mg. The amount of hormone drives the efficacy, bleeding profile, and recommendations for length of use.
The 52-mg IUS has gained popularity as a highly effective, reversible contraceptive because of several advantages, including the ability to significantly decrease menstrual blood loss and improve dysmenorrhea. The US Food and Drug Administration’s first approval of a 52-mg IUS was for Mirena for a 5-year duration. In 2009, an indication for treatment of heavy menstrual bleeding was added.3 The second levonorgestrel 52-mg IUS, Liletta, was initially approved for 3 years for contraceptive use in 2015 and, as of October 2019, is approved for up to 6 years.4
The drive to bring Liletta to market as a second levonorgestrel 52-mg IUS was based on cost barriers. Unintended pregnancies, unintended births, and abortions are disproportionately high in women of low socioeconomic status (SES).5 While reasons for these findings are multifactorial, there is an established relationship between low SES and less effective use of contraception.5 When cost is removed as a barrier, use of long-acting reversible contraception (LARC) increases dramatically.1,6,7
Under the Health Resources & Services Administration (HRSA), manufacturers participating in Medicaid can provide drugs at significantly reduced prices to eligible organizations/entities under the 340B Drug Pricing Program.8 Medicines360, the non-profit women’s health pharmaceutical company that brought Liletta to the US market, participates in the 340B Program and offers a price approximately three times lower than for Mirena.9,10 This significantly lower cost puts less burden on clinics and providers to stock the device and allows immediate access, which can help eliminate the need for multiple visits for IUD insertion.11 Immediate access improves IUD utilization, especially in women with public insurance, who will only receive an IUD about half the time when two visits are required.11
A real-life assessment of this lower-cost levonorgestrel 52-mg IUS option at several Title X clinics in Utah resulted in an immediate increase in uptake.12 The low cost is financially supported through private sector sales, a model like the Toms Shoes and Bombas socks, wherein private sector sales support the ability for low or no cost in the public sector. As a medical community, this opportunity allows all providers to participate in efforts to provide equitable care and expand access.
Liletta has a T-shaped polyethylene frame with the same dimensions as Mirena.3,4 The inserters differ slightly; the reloadable Liletta inserter is 2 cm longer than the non-reloadable Mirena one, and the Mirena inserter is slightly narrower than the Liletta inserter (4.3 mm vs. 4.8 mm). Despite these differences, reported successful insertion rates from phase 3 trials are 98% to 99% for both products.13,14 The vertical stem of the IUS contains a reservoir of levonorgestrel 52 mg covered by a release rate-controlling membrane.4,15 Liletta produces an initial release rate of 19.5 µg/day, which decreases slowly over time to 9.8 µg/day at the end of 5 years, mirroring the release rate of Mirena.15 For comparison, the levonorgestrel 13.5-mg IUS release rate at the end of its 3-year duration is 5 µg/day.16
The calculated estimated release rates based on this information support using Liletta for contraception beyond 5 years.15 Liletta is under study in a prospective phase 3 clinical trial aimed at extending the approved duration of the levonorgestrel 52-mg IUS and evaluating the potential non-contraceptive benefits or side effects of the device among a diverse US population.14,15,17-22 This review provides key findings of the ongoing clinical trial and important discussion points that can be referenced during patient counseling to augment the shared decision-making process in contraceptive method selection.
ACCESS IUS was designed to assess the efficacy and safety of Liletta among a diverse population of women in the United States. It is a multicenter, phase 3, open-label clinical trial conducted at 29 sites in the United States including public, private, and university institutions. Of 1751 women, 1600 participants were aged 16 to 35 years and included in efficacy assessments and 151 participants aged 36 to 45 years were included for overall safety evaluation. The primary outcome was on-treatment pregnancy, defined as any pregnancy with a date of conception beginning with the day of Liletta placement and through 7 days after IUS discontinuation.14,15,17-22
Of the 1751 women enrolled, successful placement among women who had attempted IUS placement was 98.7%.17 Reasons for unsuccessful placement included inability to sound the uterus (n=15, 0.9%) and uterine measurement by sounding less than 5.5 cm (n=2, 0.1%). There were two pregnancies in the first year – one intrauterine pregnancy after Liletta IUS expulsion and one ectopic pregnancy associated with a uterine perforation. The Pearl Index (number of pregnancies per 100 woman-years) is 0.15 (95% CI 0.02 – 0.55) through year 1.14 By the end of the fifth year, there were nine total pregnancies in over 1500 women, representing over 6300 28-day cycles.18
Of the nine pregnancies, six were ectopic, resulting in an ectopic pregnancy rate through 5 years of 0.13 per 100 woman-years.18 There were no pregnancies reported year 6.17 Pregnancy rates are presented in Table 1.17 Based on these data, the FDA approved Liletta to be utilized for pregnancy prevention for 6 years in October 2019, and the study is ongoing through 10 years of IUS use.17
In addition to its high efficacy in pregnancy prevention, Liletta has also been extensively studied to evaluate its bleeding profile during use. Amenorrhea secondary to hormonal contraception is often a
desirable characteristic, as evidenced in the ACCESS IUS trial in which only one participant discontinued Liletta (in year 2 of use) due to amenorrhea.18 Mirena is reported to have a 20% amenorrhea rate in the first year of use 3 but generalizability is limited due to the skewed population of normal-weight, multiparous, white women who had used an intrauterine method previously.21 So, investigators used the ACCESS IUS data to evaluate amenorrhea and bleeding patterns in detail over the first year of use.21
In the first year, 28 women (1.8%) discontinued levonorgestrel IUS use for bleeding complaints. Among women who had not previously used a levonorgestrel IUS, amenorrhea rates were 17%, which was the same rate at 9 and 12 months.21 Among women using a levonorgestrel IUS prior to enrollment, the amenorrhea rates are 35% at 9 and 12 months.21 Amenorrhea rates in levonorgestrel 52-mg IUS users continue to rise over 6 years. At the end of 2 and 3 years, 27% and 36% of users reported amenorrhea the previous 90 days of years 2 and 3, respectively.22 The rate remains about 40% in years 4, 5, and 6.17,18
Levonorgestrel 52-mg IUS use is also notable for other decreased uterine bleeding patterns. Because these bleeding patterns can be more subjective, the Besley definitions provide an objective guide for measurements of change over time (Table 2).22,23
Prevalence of amenorrhea and infrequent, frequent, irregular, and prolonged bleeding are described in Table 3. It is common for users to experience frequent, irregular, and/or prolonged bleeding during the first 3 months, which transitions to less frequent, less prolonged bleeding by 6 months and beyond (Table 3).22 While direct comparisons between IUS products with different levonorgestrel amounts are difficult due to varied study designs and populations, both levonorgestrel 13.5-mg and 19.5-mg IUS devices are noted to have lower rates of amenorrhea and infrequent bleeding compared to the 52-mg IUS.16,22,24 This bleeding pattern information is essential for providing accurate information for patients considering levonorgestrel 52-mg IUS use.
Mirena is currently indicated for treatment of heavy menstrual bleeding (HMB) in the United States and Liletta carries the same indication in all countries other than the United States.3,25 Liletta use increases hemoglobin and serum ferritin levels,26 and in a randomized trial comparing Mirena and Liletta over 12 months in women with HMB, there were no differences in mean blood loss, ferritin, or hemoglobin values between the two products.27
HMB is quantitatively defined as ≥ 80 mL per cycle,20,28 but subjective perception of it is commonly used for diagnosis in clinical practice.29 Bleeding changes in women who subjectively report HMB have been evaluated in Liletta users. Among women using Liletta for contraception who self-report HMB at baseline, 75% reported absence of it by the end of the first cycle (28 days). By 6 months, 92% reported absence of HMB, which rose to 97% at the end of 2 years. By 1 and 2 years, 51% and 64%, respectively, reported their bleeding as amenorrhea or spotting.20
Common adverse events (AEs) occurring during Liletta use for 6 years or more included vaginal bacterial infection (17.4%), vulvovaginal mycotic infection (16.6%), and urinary tract infections (16.9%).17 Uterine perforation occurred in two participants (0.1%), both of which were identified in the first year of use.18
Because women can experience many events over years of use, discontinuation is a more tangible outcome to evaluate. Overall, in subjects followed for up to 8 years of use, 329 (19.2%) discontinued the study due to an AE.17 The most common AEs leading to discontinuation and their frequencies are listed in Table 4. Partial or complete expulsion was the most common reason, occurring in 4% of Liletta users, 73% of which occurred during the first year of IUS use.17,18 Expulsion rates were similar to previously reported values30 and three times more common in multiparous compared to nulliparous individuals.18 Overall, only 8.4% of women in the Liletta trial discontinued for a non-expulsion AE.
The most common events (≥ 1%) were bleeding complaints, acne, dysmenorrhea, and weight increase.17 Of note, ovarian cysts had been commonly reported in Mirena trials, primarily because those studies included enlarged asymptomatic cysts which were identified during required study ultrasound evaluations.31,32 The Liletta trial only evaluated symptomatic women, reporting an ovarian cyst in 78 participants (4.5%), of whom only six (0.3%) requested IUS removal.18 One (0.06%) of the ovarian cysts identified required surgical intervention.18
Another important observation from this trial is the very low risk of infection with contemporary IUS insertion practice. In this prospective trial, participants could have same-day Liletta placement and did not have to defer for sexually transmitted infection (STI) testing results. Investigators treated IUS users found to have positive testing after IUS insertion.
Pelvic infection was diagnosed in 14 participants (0.8%) during up to 8 years of follow-up, including two diagnosed after year 4.17 These results further support same-day IUS insertion and outpatient antibiotic treatment for positive test results without concurrent removal of IUS and overall very low risk of infection with extended use.17,19
ACCESS IUS is a robust, ongoing phase 3 clinical trial that continues to update clinicians about Liletta. Trial investigators have reported efficacy rates up to 6 years, which is the current FDA-approved duration, with plans to continue the study to provide data through 10 years. Prospective data improve the understanding of bleeding patterns, including amenorrhea rates, and side effects and complications leading to discontinuation. These and future data will improve clinicians’ ability to counsel effectively and provide general expectations regarding a high-efficacy contraception option.