1.1 Contraception

LILETTA is indicated for prevention of pregnancy for up to 8 years.

1.2 Heavy Menstrual Bleeding

LILETTA is indicated for the treatment of heavy menstrual bleeding for up to 5 years in patients who choose to use intrauterine contraception as their method of contraception; replace after the end of the fifth year if continued treatment of heavy menstrual bleeding is needed.

2.1 Dosing Over Time

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.

For contraception, remove LILETTA 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.

For treatment of heavy menstrual bleeding, replace LILETTA by the end of the fifth year if continued use is needed.

2.2 Timing of Insertion

Refer to Table 1 for instructions on when to start use of LILETTA.

2.3 Insertion Instructions

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.

Figure 1a: 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:

• the cervix is unable to be properly visualized
  
• the uterus cannot be adequately instrumented (during sounding)
  
• the uterus sounds to less than 5.5 cm

Preparation for Insertion

Ensure all needed items for LILETTA insertion are readily available:

• Gloves
  
• Sterile speculum
  
• Sterile uterine sound
  
• Sterile tenaculum
  
• Antiseptic solution
  
• LILETTA with inserter tray, sealed with a peel-off lid
  
• Sterile, blunt-tipped scissors

Additional items may be useful:

• Local anesthesia, needle, and syringe
  
• Sterile os finder and/or cervical dilators
  
• Ultrasound with abdominal probe

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.

Insertion Procedure

The overall insertion process is conducted in 5 steps.

Step 1 – Preparation of Patient for Insertion

• With the patient comfortably in lithotomy position, do a bimanual exam to establish the size, shape, and position of the uterus and to evaluate any signs of uterine infection.
  
• Gently insert a speculum to visualize the cervix.
  
• Thoroughly cleanse the cervix and vagina with antiseptic solution.
  
• Administer cervical anesthetic, if needed.
  
• Apply a tenaculum to the cervix and use gentle traction to align the cervical canal with the uterine cavity. If the uterus is retroverted, it may be more appropriate to grasp the lower lip of the cervix. Keep the tenaculum in position and maintain gentle traction on the cervix throughout the insertion procedure.
  
• Carefully sound the uterus to measure its depth.
  
• The uterus should sound to a depth of at least 5.5 cm. Insertion of LILETTA into a uterine cavity that sounds to less than 5.5 cm may increase the incidence of expulsion, bleeding, pain, perforation, and possibly pregnancy. LILETTA should not be inserted if the uterus sounds to less than 5.5 cm.
  
• After ascertaining that the patient is appropriate for LILETTA, replace contaminated glove(s) and open the packaging containing LILETTA, noting the lot number.

Step 2 – Opening the Sterile LILETTA Packaging

• Remove the sealed tray containing LILETTA from the box.
  
• Inspect the sealed tray and do not use the product if the packaging, inserter, or IUS is damaged.
  
• Lay the tray on a flat surface with the peel-off lid side up.
  
• Remove peel-off lid.

Step 3 – Loading LILETTA into the Inserter

• To remove the inserter from the tray, grasp the handle below the sliders and twist gently (Figure 3).
  • NOTE: Do not attempt to remove the inserter by pulling on the tube.

Figure 3: Removing Inserter from Tray

• Ensure both sliders (labeled 1 and 2) are fully forward (Figure 4):
  • The BLUE slider (labeled with the number 1) has a single line marking that will align with the handle’s single line marking.
    
  • The GREEN slider (labeled with the number 2) has a double line marking that will align with the handle’s double line marking.

• Grip the handle keeping your thumb or finger in the groove of the BLUE slider (over the numeral 1) and apply forward pressure while ensuring both sliders are fully forward.

Figure 4: Sliders Completely Forward for Loading LILETTA

• Load LILETTA into the inserter:
  • Ensure the arms of the IUS are horizontal (aligned to the horizontal plane of the handle and flange); adjust the rotation of the IUS as needed using the flat sterile surface of the tray.
    
  • While maintaining forward pressure on the BLUE slider, gently pull the threads straight back to load LILETTA into the insertion tube. Ensure even tension is applied to both threads when pulling.
    
  • Pull the threads upward or downward to lock the threads into the cleft at the bottom end of the handle (Figure 5); you must lock the threads in the cleft to prevent the IUS from moving out of the top of the insertion tube. Once the threads are locked in the cleft, stop holding the threads.
    
  • After the IUS is loaded, continue to sustain forward pressure on the BLUE slider to maintain a hemispherical dome with the tips of the IUS.

• When correctly loaded, the IUS is completely within the insertion tube with the tips of the arms forming a hemispherical dome at the top of the tube (Figure 6).
  
• If the IUS is not correctly loaded, do not attempt insertion.
  
• To re-load LILETTA:
  ▪ Pull the BLUE slider back with your thumb until the groove becomes aligned with the GREEN slider to release the IUS.
  ▪ Manually pull the threads out of the cleft.
  ▪ Return the BLUE slider to the forward position and repeat the loading steps.

Figure 5: Locking the Threads in Cleft

Figure 6: Close-up of Hemispherical Dome at Tip of Tube

• Adjust the flange to the measured uterine depth based on sounding. To adjust, place the flat side of the flange in the tray notch (Figure 7) or against a sterile edge inside of the tray. Slide the insertion tube as necessary to move the flange to the correct measurement. Ensure the flat sides of the flange are in the same horizontal plane as the handle. If, at any step, there is a need to touch the flange or another sterile surface, sterile gloves should be used.

Figure 7: Adjusting the Flange

• If an adjustment to the curvature of the insertion tube is required to accommodate the anatomical orientation of the uterus, you may bend or straighten the insertion tube, but do not touch above the flange unless using sterile gloves. When bending the tube, avoid sharp bends to prevent kinking.
  
• Once the flange has been properly positioned, avoid contact of flange against objects that can change its position (e.g., tray, speculum, tenaculum, etc.).

Step 4 – Inserting LILETTA into the Uterus

• Apply gentle traction on the tenaculum and continue to apply forward pressure on the BLUE slider while inserting the loaded insertion tube through the cervical os. Advance the tube until the upper edge of the flange is 1.5-2 cm from the external cervical os (Figure 8). Maintain forward pressure on the BLUE slider throughout the insertion process.
  ○ DO NOT advance flange to the cervix at this time.
  ○ DO NOT force the inserter. If necessary, dilate the cervical canal.

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

• Wait 10-15 seconds to allow for the arms of the IUS to fully open.
  
• Without moving the sliders, advance the inserter until the flange touches the cervix. If fundal resistance is encountered, do not continue to advance. LILETTA is now in the fundal position (Figure 10).
  
• Note: Fundal position is important to prevent expulsions.

Figure 10: Move LILETTA into the Fundal Position

Step 5 – Releasing LILETTA and Procedure Completion

• While holding the inserter steady and maintaining its position relative to the cervix, move both sliders (BLUE and GREEN) together while maintaining the joint slider recess down toward the number 3 on the handle (Figure 11) until a click is heard and the GREEN indicator at the bottom of the handle is visible, signifying deployment (Figure 12).

Figure 11: Releasing LILETTA from the Inserter Tube

• Look at the cleft to ensure the threads were properly released (Figure 12); if not released or if a click is not heard, grasp the threads and gently pull the threads out of the cleft.

Figure 12: Green Indicator Visible and Threads Released from Cleft

• Withdraw the inserter from the uterus.
  
• Use blunt-tipped sharp scissors to cut the IUS threads perpendicular to the thread length, leaving about 3 cm outside of the cervix (Figure 13). Note: Do not cut threads at an angle as this may leave sharp ends.
  
• Do not apply tension or pull on the threads when cutting to prevent displacing the IUS.

Figure 13: Cut the Threads about 3 cm from the Cervix

• Insertion of LILETTA is now complete.

Important information to consider during or after insertion:

If you suspect the IUS is not in the correct position, conduct the following procedures:

• Check insertion with an ultrasound or other appropriate radiologic test.
  
• If incorrect insertion is confirmed, remove LILETTA. Do not reinsert the same LILETTA IUS after removal.

Difficult Insertion

If insertion is difficult because the uterus cannot be appropriately instrumented, consider the following measures:

• Use of cervical anesthesia to make sounding and manipulation more tolerable.
  
• Use of dilators to dilate the cervix if needed to allow passage of the sound or inserter.
  
• Abdominal ultrasound guidance during dilation and/or insertion.
  
• If there is clinical concern, exceptional pain, or bleeding during or after insertion, take appropriate steps, such as physical examination and ultrasound, immediately to exclude uterine perforation [see Warnings and Precautions (5.5)].

2.4 Patient Counseling and Record-Keeping

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.

2.5 Patient Follow-Up

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.

2.6 Removal of LILETTA

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.

For contraception, 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.

For treatment of heavy menstrual bleeding, LILETTA should be replaced at the end of the fifth year if continued treatment is needed.

Preparation for Removal

Ensure all needed items for LILETTA removal are readily available:

• Gloves
  
• Sterile speculum
  
• Sterile forceps

Additional items may be required:

• Local anesthetic, needle, and syringe
  
• Sterile os finder and/or cervical dilators
  
• Ultrasound with abdominal transducer
  
• Sterile tenaculum
  
• Antiseptic solution
  
• Sterile long, narrow forceps or intrauterine thread retriever

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.

Removal Procedure

With the patient comfortably in lithotomy position, place a speculum and visualize the cervix.

When the threads of LILETTA are visible:

• Remove the IUS by applying gentle traction on the threads with forceps (Figure 14).
  
• The arms of the device will fold upward as it is withdrawn from the uterus.
  
• If the IUS cannot be removed with gentle traction on the threads, perform an ultrasound examination to confirm location of the IUS, including assessment for embedment in the myometrium or partial- or total-perforation. If the IUS is in the uterus, use long, narrow forceps to grasp LILETTA. Consider use of a tenaculum, cervical anesthesia, cervical dilators, and/or ultrasound guidance as needed.
  
• After removal, examine the system to ensure it is intact.

If the threads of LILETTA are not visible:

• Determine location of the IUS and exclude embedment or perforation by ultrasound examination [see Warnings and Precautions (5.10)].
  
• If the IUS is in the uterine cavity, thoroughly cleanse the cervix and vagina with antiseptic solution. Use a thread retriever to capture the threads or a long, narrow forceps (e.g., Alligator forceps) to grasp LILETTA. Consider use of a tenaculum, cervical anesthesia, cervical dilators, and/or ultrasound guidance as needed. If LILETTA cannot be removed using the above techniques, consider hysteroscopic evaluation for removal.
  
• If the IUS is not in the uterine cavity, consider an abdominal x-ray or CT scan to evaluate if the IUS is in the abdominal cavity. Consider laparoscopic evaluation for removal, as clinically indicated.
  
• After removal, examine the system to ensure it is intact.

Figure 14: Removal of LILETTA

2.7 Continuation of Contraception after Removal

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.

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 Abortion

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.

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.

*Amenorrhea is defined as no bleeding and/or spotting.

*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.

*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.

*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.

5.9 Breast Cancer

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.

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 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 leiomyomas, 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:

• 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, (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.

5.11 Magnetic Resonance Imaging (MRI) Information

LILETTA is MR-Safe. LILETTA is compatible with MRI and should not interfere with imaging.

6.1 Clinical Study Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies 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 study 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 study on contraception (occurring in ≥ 5% of participants) are shown in Table 6. 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 study, 20.1% of LILETTA participants 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 study 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 study, serious adverse reactions related to LILETTA were ectopic pregnancies, ovarian cysts, and IUS perforation requiring laparoscopic surgery.

In the LILETTA clinical study on heavy menstrual bleeding, which included 105 participants who were 18- to 50-years old, the adverse reaction profile was consistent with the adverse reaction profile for LILETTA participants in the contraception study as shown in Table 6. Approximately 11% of LILETTA study participants discontinued prematurely due to an adverse reaction. The most common adverse reactions leading to discontinuation were expulsions (4.8%) and bleeding pattern alterations (3.8%).

6.2 Postmarketing Experience

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.

• Arterial thrombotic and venous thromboembolic events, including cases of pulmonary emboli, deep vein thrombosis, and stroke
  
• Hypersensitivity (including rash, urticaria, and angioedema)
  
• Increased blood pressure
  
• Dizziness
  
• Device breakage

8.1 Pregnancy

Risk Summary

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. There have been isolated cases of virilization of the external genitalia of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place. 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.

8.2 Lactation

Risk Summary

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)].

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Assess pregnancy status prior to inserting LILETTA, as recommended [see Dosage and Administration (2.2) and Use in Specific Populations (8.1)].

8.4 Pediatric Use

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 study on contraception 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.

8.5 Geriatric Use

LILETTA is not indicated in patients after menopause and has not been studied in this population.

8.6 Hepatic Impairment

No studies were conducted to evaluate the effect of hepatic disease on the disposition of LNG released from LILETTA [see Contraindications (4)].

11.1 LILETTA

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.

Figure 15: Diagram of LILETTA

11.2 Inserter

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.

Figure 16: Diagram of Inserter

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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 studies with other LNG-releasing IUSs with an LNG release rate similar to LILETTA, approximately 45-75% of menstrual cycles were ovulatory.

12.3 Pharmacokinetics

Absorption

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 clinical study on contraception, systemic plasma LNG concentrations were assessed in a subset of participants through Month 30 and in all participants in the study at Month 36 and after. Plasma LNG concentrations following insertion of LILETTA are shown in Table 7.

Distribution

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.

Elimination

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.

Metabolism

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.

Excretion

About 45% of LNG and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates.

Specific Populations

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)].

BMI/Body Weight:

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[see Warnings and Precautions (5.9)]

14.1 Clinical Study on Contraception

The efficacy of LILETTA for contraception was studied in a multicenter, randomized, open-label clinical study 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: White 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 study had no limit on weight (minimum or maximum) or 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 8 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 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.

14.2 Clinical Study on Treatment of Heavy Menstrual Bleeding

The efficacy of LILETTA in the treatment of heavy menstrual bleeding was studied in a non-comparative, open-label clinical study conducted in the US. The study enrolled 105 generally healthy participants 18 to 50 years of age, with no contraindications to LILETTA, and with confirmed heavy menstrual bleeding (≥ 80 mL menstrual blood loss [MBL] per menses) determined using the alkaline hematin method. Participants with any structural (e.g., leiomyomas > 2 cm in greatest diameter or more than 3 leiomyomas > 1.5 cm in greatest diameter) or diagnosed pathophysiologic conditions that may cause heavy uterine bleeding were excluded.

The study population was 64.8% White, 23.8% African American, and 11.4% Other; 9.5% of enrolled participants were of Hispanic ethnicity. The median BMI was 29.7 kg/m2 (with 23.8% overweight and 48.6% obese). The median baseline MBL was 143.2 mL.

The primary efficacy endpoint was the proportion of women with successful treatment, defined as (1) an end-of-study MBL volume < 80 mL and (2) ≥ 50% reduction in MBL from baseline to end-of-study.

Treatment outcomes with LILETTA are summarized in Figures 17 and 18. The proportion of participants meeting both criteria defining successful treatment was 80% at the end of the study, with a 95% confidence interval of 71-88% (Figure 17). The quantitative reduction in median MBL volume from baseline to mid-study and to end-of-study is shown in Figure 18. The median MBL percent reduction from baseline to mid-study was 91% and to end-of-study was 96%.

Figure 17: Proportion of Participants with Successful Treatment of HMB Over Time	Figure 18: Median Menstrual Blood Loss (MBL) Over Time