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LILETTA- levonorgestrel intrauterine device Allergan, Inc.
LILETTA is a progestin-containing intrauterine system indicated for prevention of pregnancy for up to 8 years. (1)
One intrauterine system consisting of a T-shaped polyethylene frame with a drug reservoir containing 52 mg LNG, packaged within a sterile inserter. (3)
The most common adverse reactions reported in clinical trials (> 10% users) are vulvovaginal mycotic infections, vaginal bacterial infections, acne, and nausea or vomiting. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
LILETTA is indicated for prevention of pregnancy for up to 8 years.
LILETTA contains 52 mg of levonorgestrel (LNG). Initially, LNG is released in vivo at a rate of approximately 20 mcg/day. This rate decreases progressively to approximately 6.5 mcg/day after 8 years. The average in vivo release rate of LNG is approximately 13.5 mcg/day over a period of 8 years.
LILETTA can be removed at any time but must be removed by the end of the eighth year. LILETTA can be replaced at the time of removal with a new LILETTA if continued contraceptive protection is desired.
Refer to Table 1 for instructions on when to start use of LILETTA.
LILETTA (Figure 1a) is provided in a tray, sealed with a peel-off lid and is inserted into the uterine cavity with the provided inserter (Figure 1b) [see Description (11)] by carefully following the insertion instructions. Do not use if the seal of the sterile package is broken or appears compromised. Use strict aseptic techniques throughout the insertion procedure [see Warnings and Precautions (5.3)]. LILETTA is for single use only.
Note: The inserter provided with LILETTA (see Figure 1b) and the Insertion Instructions in this section are not applicable for immediate insertion after childbirth or second-trimester abortion or miscarriage. For immediate insertion, remove LILETTA from the inserter by pulling LILETTA out of the top of the inserter and insert according to accepted practice.
LILETTA Intrauterine Contraceptive System (IUS)
Figure 1b: LILETTA IUS with Inserter
The LILETTA IUS is packaged partially preloaded within the inserter. The threads are passed through the insertion tube and exit through an opening in the handle at the cleft.
The handle of the inserter contains a BLUE slider labeled with the number 1 and a GREEN slider labeled with the number 2. The handle is labeled with the number 3. The sliders are labeled with the numbers 1 and 2, and the handle is labeled with the number 3 to assist with the insertion process (Figure 2). Moving the sliders achieves the positions required to complete the insertion process.
Figure 2: Inserter Sliders
Planning for Insertion
LILETTA should only be inserted by a trained healthcare professional. Healthcare professionals should become thoroughly familiar with the product, product educational materials, product insertion instructions, prescribing information, and patient labeling before attempting insertion of LILETTA.
Obtain a complete medical and social history to determine conditions that might influence the selection of LILETTA for contraception. If indicated, perform a physical examination and appropriate tests for genital or sexually transmitted infections.1 [See Contraindications (4) and Warnings and Precautions (5.4, 5.10)].
Check the expiration date on the box before opening it. Do not insert LILETTA after the expiration date.
Visually inspect the packaging containing LILETTA to verify that the packaging has not been damaged (e.g., torn, punctured, etc.). If the packaging has any visual damage that could compromise sterility, do not use the unit for insertion [see Warnings and Precautions (5.3)]. Complete the pelvic examination, speculum placement, tenaculum placement, and sounding of the uterus before opening the LILETTA packaging.
Do not open the packaging to insert LILETTA if the following clinical findings occur:
Preparation for Insertion
Ensure all needed items for LILETTA insertion are readily available:
Additional items may be useful:
Exclude pregnancy and confirm that there are no other contraindications to the insertion and use of LILETTA.
Follow the insertion instructions exactly as described to ensure proper insertion.
If you encounter cervical stenosis at any time during uterine sounding or LILETTA insertion, use cervical dilators, not force, to overcome resistance. If necessary, dilation, sounding, and insertion may be performed with ultrasound guidance.
Insertion may be associated with some pain and/or bleeding or vasovagal reactions (e.g., diaphoresis, syncope, bradycardia, or seizure), especially in patients with a predisposition to these conditions. Consider administering analgesics prior to insertion.
Use aseptic technique during the entire insertion procedure.
The overall insertion process is conducted in 5 steps.
Step 1 – Preparation of Patient for Insertion
Step 2 – Opening the Sterile LILETTA Packaging
Step 3 – Loading LILETTA into the Inserter
Figure 3: Removing Inserter from Tray
Figure 4: Sliders Completely Forward for Loading LILETTA
Figure 5: Locking the Threads in Cleft
Figure 6: Close-up of Hemispherical Dome at Tip of Tube
Figure 7: Adjusting the Flange
Step 4 – Inserting LILETTA into the Uterus
Figure 8: Advancing Insertion Tube until Flange is 1.5 to 2 cm from the External Cervix
● Using your thumb or finger, gently slide only the BLUE slider back. You will feel slight resistance initially to move the BLUE slider out of its starting position. Continue to move the BLUE slider back until you feel slight resistance again as the BLUE and GREEN sliders will merge together to form a joint slider recess. Do not move the BLUE slider any more than is necessary to create the recess. Maintain the GREEN slider so that the double line markings on the slider and the insertion handle remain aligned (Figure 9). This will allow the IUS arms to open in the lower uterine segment. Do not pull the sliders back any further as this could result in premature release of the IUS at the incorrect location.
Figure 9: Releasing and Opening the Arms of the IUS
Figure 10: Move LILETTA into the Fundal Position
Step 5 – Releasing LILETTA and Procedure Completion
Figure 11: Releasing LILETTA from the Inserter Tube
Figure 12: Green Indicator Visible and Threads Released from Cleft
Figure 13: Cut the Threads about 3 cm from the Cervix
Important information to consider during or after insertion:
If you suspect the IUS is not in the correct position, conduct the following procedures:
If insertion is difficult because the uterus cannot be appropriately instrumented, consider the following measures:
Counsel the patient on what to expect following LILETTA insertion. Discuss expected bleeding patterns with LILETTA use. Review the signs and symptoms associated with infection, perforation, and expulsion that may occur with use of LILETTA [see Patient Counseling Information (17)].
Prescribe analgesics, if indicated.
The healthcare professional should consider re-examining and evaluating patients 4 to 6 weeks after insertion and during routine care, or more frequently if clinically indicated. The IUS threads should be checked during each evaluation.
Planning and Timing of Removal
If pregnancy is desired, LILETTA can be removed at any time.
If pregnancy is not desired, LILETTA can be removed at any time; however, a contraception method should be started prior to removal of LILETTA [see Dosage and Administration (2.5)]. Counsel patients that they are at risk of pregnancy if they had intercourse in the week prior to removal without use of a backup contraceptive method.
LILETTA should be removed after 8 years. LILETTA can be replaced at the time of removal with a new LILETTA if continued contraceptive protection is desired.
Preparation for Removal
Ensure all needed items for LILETTA removal are readily available:
Additional items may be required:
Removal may be associated with some pain and/or bleeding or vasovagal reactions (e.g., syncope, bradycardia, or seizure), especially in patients with a predisposition to these conditions.
After removal of LILETTA, examine the system to ensure that it is intact. The hormone cylinder may slide over and cover the horizontal arms, giving the appearance of missing arms. This does not require further intervention if the system is verified to be intact.
Breakage, embedment in the myometrium, or perforation of LILETTA can make removal difficult [see Warnings and Precautions (5.5)]. IUS breakage may be associated with removal. Analgesia, paracervical anesthesia, cervical dilation, alligator forceps or other grasping instrument, or hysteroscopy may assist in removal.
With the patient comfortably in lithotomy position, place a speculum and visualize the cervix.
When the threads of LILETTA are visible:
If the threads of LILETTA are not visible:
Removal of LILETTA
If a patient wishes to continue using LILETTA or another intrauterine contraceptive, insertion can occur immediately after removal.
If a patient with regular cycles wants to start a different birth control method, time the removal and initiation of a new method to ensure continuous contraception. Either remove LILETTA during the first 7 days of the menstrual cycle and start the new method or start the new method at least 7 days prior to removing LILETTA 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 LILETTA removal.
If LILETTA is removed but no other contraceptive method has already been started, the new contraceptive method can be started on the day LILETTA is removed. The patient should use a backup barrier method of contraception (e.g., condoms) or abstain from vaginal intercourse for 7 days to prevent pregnancy.
LILETTA is a levonorgestrel-releasing intrauterine system consisting of a T-shaped polyethylene frame with a drug reservoir containing 52 mg levonorgestrel, packaged within a sterile inserter.
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 fibroids, 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 neoplasia
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)].
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 trial 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. 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).
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:
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 Pregnancy
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.
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.
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 trial 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.
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 trial, 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 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.
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 trial, which excluded breastfeeding participants, was 0.1%.
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 4.1% 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. 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.
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. 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.
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 trial. Discuss this risk with patients, as indicated.
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.
The amenorrhea rates observed in the LILETTA clinical trial are shown in Table 2. The bleeding and spotting days, based on 28-day cycle equivalents, are shown in Table 3. In the trial, 2.5% of participants discontinued LILETTA due to bleeding complaints.
*Amenorrhea defined as no bleeding and/or spotting
Note: Includes all LILETTA participants.
In the LILETTA clinical trial, 651 of 652 (99.8%) participants 16-35 years of age at enrollment that were evaluated experienced menses after LILETTA removal. This excludes twelve participants (9 became pregnant, 2 had a hysterectomy, and 1 had ovulatory dysfunction).
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 patients unless indicated by other signs of pregnancy or pelvic pain.
Patients 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 an LNG-releasing IUS.
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 patients 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 patients 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 patient is at increased risk of pelvic infection (e.g., unprotected sex, history of PID, or acquired immune deficiency syndrome [AIDS]). 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:
Consider removing LILETTA if any of the following conditions arise during use [see Contraindications (4)]:
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, (e.g., 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.
LILETTA is MR-Safe. LILETTA is compatible with MRI and should not interfere with imaging.
The following serious or important adverse reactions are discussed 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 or Endometritis [see Warnings and Precautions (5.4)]
Perforation [see Warnings and Precautions (5.5)]
Expulsion [see Warnings and Precautions (5.6)]
Ovarian Cysts [see Warnings and Precautions (5.7)]
Bleeding Pattern Alterations [see Warnings and Precautions (5.8)]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials 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 described below reflect exposure of 1,751 generally healthy participants, 16 to 45 years of age, to LILETTA in a large, multi-center contraceptive trial conducted in the US. Participants included 1,401 exposed for 1 year and 380 who completed 8 years of use; 58% were nulliparous (mean age 25.1 ± 4.3 years) and 42% were parous (mean age 30.3 ± 6.1 years). Most participants who received LILETTA were Caucasian (78.4%) or Black/African American (13.3%); 14.7% of participants were of Hispanic ethnicity. Mean BMI of LILETTA participants was 26.9 kg/m2 (range 15.8 – 61.6 kg/m2); 25.1% had a BMI ≥ 30 kg/m2 of which 5.3% had a BMI ≥ 40 kg/m2. The data cover more than 80,221 28-day cycles of LILETTA exposure. The frequencies of reported adverse drug reactions represent crude incidences.
The most common adverse reactions during the LILETTA clinical trial (occurring in ≥ 5% of users) are shown in Table 4. The most common adverse reactions during the first year of use were acne (11.4%), bacterial vaginitis (9.0%), and vulvovaginal mycotic infection (7.9%).
In the clinical trial, 20.1% of LILETTA users discontinued prematurely due to an adverse reaction. The most common adverse reactions reported by participants as reason for discontinuation were expulsion (4.1%), bleeding complaints (2.5%), acne (1.4%), dysmenorrhea (1.0%), weight increased (1.0%), mood swings (0.8%), uterine spasm (0.7%), dyspareunia (0.6%) and pelvic pain (0.6%). Two participants discontinued the clinical trial due to PID and one due to endometritis. The most common adverse reactions reported by participants as reason for discontinuation during the first year of use were expulsion (2.9%) and acne (0.7%).
In the clinical trial, serious adverse reactions related to LILETTA were ectopic pregnancies, ovarian cysts, and IUS perforation requiring laparoscopic surgery.
The following adverse reactions have been identified during post-approval use of LNG-releasing IUSs. 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.
No drug-drug interaction studies have been conducted with LILETTA.
LILETTA is contraindicated for use in pregnant patients and LILETTA may cause adverse pregnancy outcomes. If a patient becomes pregnant with LILETTA in place, there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery. Published studies report no harmful effects on fetal development associated with long-term use of contraceptive doses of oral progestins in a pregnant patient. Animal reproduction studies have not been conducted with LILETTA.
The background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
Published studies report the presence of LNG in human milk. Small amounts of progestins (approximately 0.1% of the total maternal doses) were detected in the breast milk of nursing mothers who used other LNG-releasing IUSs. Isolated cases of decreased milk production have been reported with another LNG-releasing IUS. There are no reports of adverse effects in breastfed infants with maternal use of progestin-only contraceptives. The infant’s developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LILETTA, underlying maternal conditions, and any potential adverse effects from LILETTA on the infant.
The incidence of uterine perforation appears higher in lactating patients [see Warnings and Precautions (5.5)].
Assess pregnancy status prior to inserting LILETTA, as recommended [see Dosage and Administration (2.2) and Use in Specific Populations (8.1)].
Safety and effectiveness of LILETTA have been established in females of reproductive potential. The safety and effectiveness are expected to be the same for postpubertal females under the age of 16 as for users 16 years and older. The LILETTA clinical trial included 11 participants who were 16 to 17 years of age; no differences in safety or effectiveness were identified in these participants through 8 years of use of LILETTA. Use of this product is not indicated before menarche.
LILETTA is not indicated in patients after menopause and has not been studied in this population.
No studies were conducted to evaluate the effect of hepatic disease on the disposition of LNG released from LILETTA [see Contraindications (4)].
LILETTA (levonorgestrel-releasing intrauterine system) contains 52 mg of levonorgestrel, a progestin, and is intended to provide an initial release rate of 20.4 mcg/day of levonorgestrel.
Levonorgestrel USP, (-)-13-ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one, the active ingredient in LILETTA, is the levorotatory form of norgestrel, which consists of a racemic mixture of D-(–)-norgestrel (levonorgestrel) and L-(+)-norgestrel (dextronorgestrel). It has a molecular weight of 312.45, a molecular formula of C21H28O2, and the following structural formula:
LILETTA consists of a T-shaped polyethylene frame (T-frame) with a drug reservoir around the vertical stem (Figure 15). The T-frame has a loop at one end of the vertical stem and two horizontal arms at the other end. The drug reservoir consists of a cylinder, made of a mixture of 52 mg levonorgestrel and polydimethylsiloxane (PDMS) formed from silicone base, tetra-n-propyl silicate, and stannous octoate. The drug reservoir is covered by a translucent PDMS membrane. The low-density polyethylene of the T-frame is compounded with barium sulfate, which makes it radio-opaque. A blue polypropylene monofilament removal thread is attached to an eyelet at the end of the vertical stem of the T-frame. The polypropylene of the removal thread contains a copper-containing pigment as a colorant. The components of LILETTA, including its packaging, are not manufactured using natural rubber latex.
Diagram of LILETTA
The inserter device provided with LILETTA is a single-use, disposable, sterile insertion system (tube, flange, handle; Figure 16), partially preloaded with the IUS product for intrauterine administration.
Once LILETTA has been inserted, the inserter is discarded.
Diagram of Inserter
The local mechanism by which continuously released LNG provides contraception has not been conclusively demonstrated. Studies of LNG-releasing IUSs suggest several mechanisms for pregnancy prevention: prevention of fertilization due to the thickening of the cervical mucus, which inhibits sperm passage through the cervix, and inhibition of sperm mobility and function (capacitation), and alteration of the endometrium.
LILETTA has mainly local progestogenic effects in the uterine cavity which change the endometrium and may lead to alterations in the menstrual bleeding pattern [see Warnings and Precautions (5.8)]. High local concentrations of LNG lead to morphological changes including stromal pseudo-decidualization, glandular atrophy, a leukocytic infiltration, and a decrease in glandular and stromal mitoses.
In clinical trials with other LNG-releasing IUSs with an LNG release rate similar to LILETTA, approximately 45-75% of menstrual cycles were ovulatory.
Low doses of LNG are administered into the uterine cavity with the LILETTA intrauterine delivery system. The initial in vivo release rate is 20.4 mcg/day and decreases to 17.7 mcg/day at 1 year, 15.3 mcg/day at 2 years, 13.3 mcg/day at 3 years, 11.5 mcg/day at 4 years, 10.0 mcg/day at 5 years, 8.7 mcg/day at 6 years, 7.5 mcg/day at 7 years, and 6.5 mcg/day at 8 years.
In the phase 3 clinical trial, systemic plasma LNG concentrations were assessed in a subset of participants through Month 30 and in all participants in the trial at Month 36 and after. Plasma LNG concentrations following insertion of LILETTA are shown in Table 5.
The apparent volume of distribution of LNG at steady-state following oral administration is reported to be approximately 1.8 L/kg. It is about 98.9% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin.
The elimination half-life of LNG after a single oral administration is approximately 13.9 ± 3.2 hours. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for wide individual variations in LNG concentrations seen in individuals using LNG–containing contraceptive products.
Following absorption, LNG is conjugated at the 17β-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in serum. Significant amounts of conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are also present in serum, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. In vitro studies have demonstrated that oxidative metabolism of LNG is catalyzed by CYP enzymes, especially CYP3A4.
About 45% of LNG and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates.
Racial or Ethnic Groups:
The effect of race on plasma LNG concentrations after LILETTA insertion was assessed in 731 (80%) White participants, 106 (12%) Black participants, 40 (4%) Asian participants, 8 (1%) American Indian/Alaska Native participants, and 21 (2%) multiple-race participants. Race does not appear to affect LNG concentrations following LILETTA insertion [see Clinical Studies (14)].
The effect of BMI on LNG exposure was assessed in 687 non-obese (BMI < 30 kg/m2) and 225 obese participants (BMI ≥ 30 kg/m2). Plasma LNG concentrations were approximately 21-34% lower in obese participants than in non-obese participants based on data collected from Months 36 to 96. However, since LILETTA has a mainly local progestogenic effect in the uterine cavity, the clinical relevance of the reduced systemic exposure is unclear [see Clinical Studies (14)].
Drug Interaction Studies
Contraceptive effect of LILETTA 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.
[see Warnings and Precautions (5.9)]
LILETTA was studied in a multicenter, randomized, open-label clinical trial conducted in the US that enrolled 1,910 generally healthy participants aged 16 to 45 years, 1,751 of whom received LILETTA. LILETTA was inserted in 1,011 (58%) nulliparous and 740 (42%) parous participants. Participants with a history of ectopic pregnancy, PID, or trophoblastic disease without a subsequent intrauterine pregnancy, who were less than 4 weeks post-pregnancy, had HIV, or were not in a mutually monogamous relationship at study entry were excluded. The demographic profile of enrolled participants who received LILETTA are as follows: Caucasian 78.4%, Black or African American 13.3%, Asian 3.9%, American Indian or Alaska Native 1.2%, Native Hawaiian or Other Pacific Islander 0.3%; 2.9% identified multiple races; 14.7% indicated Hispanic ethnicity. The clinical trial had no upper or lower weight or BMI limit and the BMI range was 15.8 – 61.6 kg/m2. The mean BMI of LILETTA participants was 26.9 kg/m2; 24% were overweight, 24% were obese (BMI ≥ 30 kg/m2), and 5% were morbidly obese (BMI ≥ 40 kg/m2).
The pregnancy rate calculated as the Pearl Index (PI) in participants 16 to 35 years of age, inclusive, was the primary efficacy endpoint used to assess contraceptive reliability. The PI was calculated based on 28-day equivalent exposure cycles; evaluable cycles excluded those in which back-up contraception was used unless a pregnancy occurred in that cycle. The Year 1 PI was based on two pregnancies and the cumulative 8-year pregnancy rate was calculated by the life table method, based on a total of eleven pregnancies that occurred after the onset of treatment and within 7 days after LILETTA removal or expulsion. Table 6 shows the annual PI for each of the eight years and the calculated cumulative life table pregnancy rates through years 1, 2, 3, 4, 5, 6, 7, and 8. For Year 7 and Year 8, participants who were more than 39 years of age at the beginning of the respective study year were excluded from the efficacy analysis.
*Excludes participants >39 years of age at the beginning of the respective year.
Conception rates after the removal of LILETTA were assessed and appeared consistent with conception rates in the general population of participants having regular unprotected sexual intercourse for 12 months.
Of 244 participants who desired pregnancy after study discontinuation, 63.1% conceived within 6 months after removal of LILETTA and 83.2% conceived within 12 months after removal of LILETTA.
Centers for Disease Control and Prevention (CDC), (2019). CDC STD Treatment [online] Available at: https://www.cdc.gov/std/treatment-guidelines/pid.htm
LILETTA (levonorgestrel-releasing intrauterine system), containing 52 mg levonorgestrel, is supplied partially preloaded within the inserter and packaged in a clear plastic tray with lid. LILETTA is available in a carton of one sterile unit. NDC # 0023-5858-01.
LILETTA is supplied sterile. LILETTA is sterilized with ethylene oxide. Do not re-sterilize. Do not use if the packaging is damaged, or if the packaging is opened. Insert before the end of the month shown on the packaging. Store at 20°C – 25°C (68°F – 77°F), with excursions permitted between 15°C – 30°C (59°F – 86°F) [See USP Controlled Room Temperature]. Store the sealed tray with peel-off lid in outer carton until use to protect from light.
Advise patients to read the FDA-approved patient labeling (Patient Information).
Advise patients that this product does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs).
Advise patients about the risks of ectopic pregnancy, including the loss of fertility. Advise them to recognize and report promptly to their healthcare professional any symptoms of ectopic pregnancy, including lower abdominal pain, especially in association with missed periods [see Warnings and Precautions (5.1)].
Advise patients about the following concerns and precautions if pregnancy occurs while using LILETTA:
Advise patients that severe infection or sepsis, including Group A streptococcal sepsis (GAS), can occur within the first few days after LILETTA is inserted. Advise them to contact a healthcare professional immediately if they develop severe pain or fever shortly after LILETTA is inserted [see Warnings and Precautions (5.3)].
Advise patients about the possibility of PID or endometritis and that these infections can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Advise the patient to recognize and report to their healthcare professional any of the following signs and symptoms of possible infection [see Warnings and Precautions (5.4)]:
Advise patients that perforation 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. Advise them that if perforation occurs, LILETTA will have to be located and removed. Surgery may be required. Advise them that delayed detection or removal of LILETTA in case of perforation may have the following results [see Warnings and Precautions (5.5)]:
Review with patients the signs and symptoms of LILETTA expulsion. Advise patients on how they can check that the threads still protrude from their cervix, and not to pull on them. Advise them that there is no contraceptive protection if LILETTA is displaced or expelled [see Warnings and Precautions (5.6)].
Advise patients that excessive pain or vaginal bleeding during insertion, worsening pain or bleeding after insertion, or the inability to feel the threads may occur with perforation and expulsion [see Warnings and Precautions (5.5, 5.6)].
Advise patients regarding the risk of ovarian cysts and that cysts can cause clinical symptoms including pelvic pain, abdominal pain or dyspareunia and infrequently will need surgery [see Warnings and Precautions (5.7)].
Advise patients that irregular or prolonged bleeding and spotting, and/or cramps may occur during the first three to six months after insertion. If their symptoms continue or are severe, they should report them to their healthcare professional [see Warnings and Precautions (5.8)].
Advise patients to contact their healthcare professional if they experience any of the following symptoms or conditions:
Inform patients that LILETTA is compatible with MRI and should not interfere with imaging [see Warnings and Precautions (5.11)].
LILETTA® and its design are registered trademarks of Odyssea Pharma SPRL, an Allergan affiliate.
Manufactured by:Odyssea Pharma, SPRL, BelgiumAn affiliated company of Allergan USA, Inc.
Distributed by: Allergan USA, Inc. Irvine, CA 92612
Marketed by:Allergan USA, Inc. Medicines360Irvine, CA 92612 San Francisco, CA 94105
© 2023 Allergan and Medicines360. All rights reserved.
This Patient Information has been approved by the U.S. Food and Drug Administration 11/2022
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The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected over dosage, the drug's identity should be verified by chemical analysis.