Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

LILETTA (NDA-206229)

(LEVONORGESTREL)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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06/29/2023 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Ectopic Pregnancy

Additions and/or revisions underlined:

…

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.

…

5.4 Pelvic Inflammatory Disease or Endometritis

Additions and/or revisions underlined:

…

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.

…

5.6 Expulsion

Additions and/or revisions underlined:

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.

…

5.7 Ovarian Cysts

Additions and/or revisions underlined:

… 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.

…

5.8 Bleeding Pattern Alterations

Additions and/or revisions underlined:

…

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.

Please refer to label to view Table 4.

…

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.

Please refer to label to view Table 5.

…

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.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

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%).

8 Use in Specific Populations

8.1 Pregnancy

Additions and or revisions underlined:

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.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

…

What is LILETTA?

…

LILETTA can also help with heavy periods, also known as heavy menstrual bleeding (HMB), for up to 5 years.
…
What if I need treatment for heavy menstrual flow for more than 5 years?
For continued treatment of heavy menstrual flow after 5 years, your healthcare professional can remove LILETTA and place a new LILETTA during the same office visit.
…
How does LILETTA work for heavy menstrual bleeding?
The hormone in LILETTA, levonorgestrel, acts by controlling the monthly development of the womb (uterus) lining, making it thinner, so that there is less bleeding every month.
…
How well does LILETTA work for treating heavy menstrual bleeding?
In the clinical trial performed in patients with heavy menstrual bleeding and treated with LILETTA, the majority of (or 8 out of 10) patients were treated successfully. That is, their
menstrual cycle blood loss was reduced to less than 80 mL and reduced by more than half by the end of treatment at six months.
Who might use LILETTA?
…

treats heavy menstrual bleeding

…

11/10/2022 (SUPPL-11)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

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)]

5 Warnings and Precautions

5.1 Ectopic Pregnancy

(Additions and/or revisions underlined)

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).

5.2 Intrauterine Pregnancy

(Additions and/or revisions underlined)

…

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.

5.4 Pelvic Inflammatory Disease or Endometritis

(Additions and/or revisions underlined)

…

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…

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).

5.5 Perforation

(Additions and/or revisions underlined)

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%.

5.6 Expulsion

(Additions and/or revisions underlined)

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.

5.7 Ovarian Cysts

(Additions and/or revisions underlined)

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.

5.8 Bleeding Pattern Alterations

(Additions and/or revisions underlined)

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.

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.

5.10 Clinical Considerations for Use and Removal

(Additions and/or revisions underlined)

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)].

6 Adverse Reactions

6.1 Clinical Trial Experience

(Additions and/or revisions underlined)

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 greater than or equal to 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 greater than or equal to 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%).

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

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

· Device breakage

· Hypersensitivity (including rash, urticaria, and angioedema)

· Increased blood pressure

· Dizziness

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

(Additions and/or revisions underlined)

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.

8.2 Lactation

Risk Summary

…

(Additions and/or revisions underlined)

The incidence of uterine perforation appears higher in lactating patients [see Warnings and Precautions (5.5)].

8.4 Pediatric Use

(Additions and/or revisions underlined)

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 6 years of use of LILETTA. Use of this product is not indicated before menarche.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to label)

Patient Information

(Extensive changes; please refer to label)

11/10/2022 (SUPPL-12)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

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)]

5 Warnings and Precautions

5.1 Ectopic Pregnancy

(Additions and/or revisions underlined)

5.2 Intrauterine Pregnancy

(Additions and/or revisions underlined)

…

Septic Abortion

Continuation of Pregnancy

5.4 Pelvic Inflammatory Disease or Endometritis

(Additions and/or revisions underlined)

…

Patients at Increased Risk for PID or Endometritis

Asymptomatic PID or Endometritis

PID or endometritis may be asymptomatic but still result in tubal damage and its sequelae. Treatment of PID or Endometritis

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.

5.5 Perforation

(Additions and/or revisions underlined)

The incidence of perforation during or following LILETTA insertion in the clinical trial, which excluded breastfeeding participants, was 0.1%.

5.6 Expulsion

(Additions and/or revisions underlined)

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

(Additions and/or revisions underlined)

5.8 Bleeding Pattern Alterations

(Additions and/or revisions underlined)

5.10 Clinical Considerations for Use and Removal

(Additions and/or revisions underlined)

Obtain a complete medical and social history, including partner status, to determine conditions that might influence the selection of an IUS for contraception.

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)].

6 Adverse Reactions

6.1 Clinical Trial Experience

(Additions and/or revisions underlined)

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

· Arterial thrombotic and venous thromboembolic events, including cases of pulmonary emboli, deep vein thrombosis, and stroke

· Device breakage

· Hypersensitivity (including rash, urticaria, and angioedema)

· Increased blood pressure

· Dizziness

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

(Additions and/or revisions underlined)

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.

8.2 Lactation

Risk Summary

…

(Additions and/or revisions underlined)

The incidence of uterine perforation appears higher in lactating patients [see Warnings and Precautions (5.5)].

8.4 Pediatric Use

(Additions and/or revisions underlined)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to label)

Patient Information

(Extensive changes; please refer to label)

10/25/2019 (SUPPL-8)

Approved Drug Label (PDF)

4 Contraindications

(additions and/or revisions are underlined)

LILETTA is contraindicated when one or more of the following conditions exist:

Pregnancy

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

Acute pelvic inflammatory disease (PID) or endometritis or a history of PID unless there has been a subsequent intrauterine pregnancy

Infected abortion in the past 3 months

Known or suspected uterine or cervical neoplasia

Known or suspected breast cancer or other hormone-sensitive cancer, now or in the past

Uterine bleeding of unknown etiology

Untreated acute cervicitis or vaginitis, including bacterial vaginosis, known chlamydial or gonococcal cervical infection, or other lower genital tract infections until infection is controlled

Acute liver disease or liver tumor (benign or malignant)

Conditions associated with increased susceptibility to pelvic infections

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.

5 Warnings and Precautions

5.1 Ectopic Pregnancy

(additions and/or revisions are underlined)

Evaluate women for ectopic pregnancy if they become pregnant with LILETTA in place because the likelihood of a pregnancy being ectopic is increased with LILETTA. Approximately half of pregnancies that occur with LILETTA 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 woman. If an ectopic pregnancy is confirmed, LILETTA should be removed.

The incidence of ectopic pregnancy in the clinical trial with LILETTA, which excluded women 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 women who have a history of ectopic pregnancy and use LILETTA is unknown. Women 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.

Women 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).

5.10 Clinical Considerations for Use and Removal

(additions and/or revisions are underlined)

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 women 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 women 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.

Ensure a previously inserted IUS has been removed prior to insertion of LILETTA.

Assess whether the woman is at increased risk of infection (e.g., leukemia, acquired immune deficiency syndrome [AIDS], IV drug abuse), or has a history of PID unless there has been a subsequent intrauterine pregnancy. LILETTA does not protect against HIV/STI transmission.

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:

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, (for example, expulsed or perforated the uterus). 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. 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

(additions and/or revisions are underlined)

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

5.2 Intrauterine Pregnancy

(additions and/or revisions are underlined)

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 woman 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 woman becomes pregnant with LILETTA in place and if LILETTA cannot be removed or the woman chooses not to have it removed, warn her 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 that she should report immediately 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.

5.4 Pelvic Inflammatory Disease or Endometritis

(additions and/or revisions are underlined)

Insertion of LILETTA is contraindicated in the presence of known or suspected PID or endometritis or a history of PID unless there has been a subsequent intrauterine pregnancy. 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.

In the clinical trial with LILETTA, pelvic infection was diagnosed in 0.8% of women. Pelvic infection was diagnosed as PID in 0.5% of women and as endometritis in 0.3% of women. Infections occurred following variable duration-of-use. One woman diagnosed with PID and two women 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.

Women 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.

Women 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 women who have multiple sexual partners, and for women whose sexual partner(s) have multiple sexual partners. Women who have had PID or endometritis are at increased risk for a recurrence or re-infection. Other risk factors for these infections include leukemia, acquired immune deficiency syndrome (AIDS), and illicit intravenous drug use.

Asymptomatic PID or Endometritis

PID or endometritis may be asymptomatic but still result in tubal damage and its sequelae. Treatment of PID or Endometritis

Following a diagnosis of PID or endometritis, or suspected PID or endometritis, perform appropriate testing for sexually transmitted infection and initiate antibiotic therapy promptly. LILETTA does not need to be removed immediately if the woman needs ongoing contraception.1 In the LILETTA clinical trial, 12 of the 14 women who developed PID or endometritis were successfully treated without removal of LILETTA (one of the 14 women developed PID 30 days after removal).

Reassess the woman in 48-72 hours. If no clinical improvement occurs, continue antibiotics and consider removal of LILETTA. If the woman wants to discontinue use, remove LILETTA after antibiotics have been started to avoid the potential risk for bacterial spread resulting from the removal procedure. Guidelines for PID or endometritis treatment are available from the Centers for Disease Control (CDC), Atlanta, Georgia.1

Actinomycosis

Actinomycosis has been associated with IUS use. Symptomatic women with known actinomycosis infection should have LILETTA removed and receive antibiotics. Actinomycetes can be found in the genital tract cultures in healthy women 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.

5.6 Expulsion

(additions and/or revisions are underlined)

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 4.0% over 6 years was reported, with a rate of 2.2% in nulliparous women and 6.2% in parous women. The majority (73.5%) occur in the first 12 months, with 25.0% occurring in the first three months and 44.1% 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 may be increased when the uterus is not completely involuted at the time of insertion. Delay LILETTA insertion a minimum of 4 weeks or until uterine involution is complete following a delivery or a second trimester abortion.

Remove a partially expelled LILETTA. If expulsion has occurred, a new LILETTA may be inserted within 7 days after the onset of a menstrual period after pregnancy has been ruled out.

5.7 Ovarian Cysts

(additions and/or revisions are underlined)

Because the contraceptive effect of LILETTA is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age using LILETTA. Sometimes atresia of the follicle is delayed and the follicle may continue to grow. 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 4.5% of subjects using LILETTA over the course of 6 years, and 0.3% of subjects 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. Discuss this risk with patients who use LILETTA.

5.8 Bleeding Pattern Alterations

(additions and/or revisions are underlined)

In the LILETTA clinical trial, amenorrhea developed in approximately 19% of LILETTA users by the end of the first year of use, 27% by the end of the second year of use, 37% by the end of the third year of use, 37% by the end of the fourth year of use, 40% by the end of the fifth year of use, and 40% by the end of the sixth year of use. In the trial, 2.3% of LILETTA subjects discontinued due to bleeding complaints. Table 2 shows the bleeding and spotting days based on 28-day cycle equivalents.

In the LILETTA clinical trial, 537 of 538 (99.8%) women evaluated experienced menses after LILETTA removal. This excludes fourteen women who became pregnant (9 women), had a hysterectomy (3 women), were considered menopausal after removal (1 woman), or had ovulatory dysfunction (1 woman).

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 women unless indicated by other signs of pregnancy or pelvic pain.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions and/or revisions are underlined)

The data described below reflect exposure of 1,751 generally healthy 16- to 45-year-old women to LILETTA in a large, multi-center contraceptive trial conducted in the US, including 1,401 exposed for 1 year and 402 subjects who completed 6 years of use; 58% were nulliparous (mean age 25.1 plus or minus 4.3 years) and 42% were parous (mean age 30.3 plus or minus 6.1 years). Most women who received LILETTA were Caucasian (78.4%) or Black/African American (13.3%); 14.7% of women were of Hispanic ethnicity.

The clinical trial had no upper or lower weight or body mass index (BMI) limit. Mean BMI of LILETTA subjects was 26.9 kg/m^2 (range 15.8 – 61.6 kg/m^2); 25.1% had a BMI greater than or equal to 30 kg/m^2 of which 5.3% had a BMI greater than or equal to 40 kg/m^2. The data cover more than 68,000 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 greater than or equal to 5% of users) are shown in Table 3. 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 contraceptive clinical trial, 19.2% of LILETTA users discontinued prematurely due to an adverse reaction. The most common adverse reactions leading to discontinuation were expulsion (4.0%) and bleeding complaints (2.3%). The most common adverse reactions leading to discontinuation during the first year of use were expulsion (2.9%) and acne (0.7%). The next most common adverse reactions causing discontinuation were acne (1.4%), dysmenorrhea (1.0%), weight increased (1.0%), menorrhagia (0.9%), mood swings (0.8%), uterine spasm (0.7%), dyspareunia (0.6%) and pelvic pain (0.6%). Two women discontinued the clinical trial due to PID and one due to endometritis.

In the clinical trial, serious adverse reactions related to LILETTA were ectopic pregnancies, ovarian cysts, and IUS perforation requiring a laparoscopic surgery.

8 Use in Specific Populations

8.2 Lactation

(additions and/or revisions are underlined)

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 women.

8.3 Females and Males of Reproductive Potential

(newly added subsection)

Pregnancy Testing

Assess pregnancy status prior to inserting LILETTA, as recommended.

8.4 Pediatric Use

(additions and/or revisions are underlined)

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 subjects that were 16 to 17 years of age; no differences in safety or effectiveness were identified in these subjects through 6 years of use of LILETTA. Use of this product is not indicated before menarche.

8.5 Geriatric Use

(additions and/or revisions are underlined)

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(extensive additions and/or revisions; please refer to labeling for complete information)

PATIENT INFORMATION

(extensive additions and/or revisions; please refer to labeling for complete information)

10/15/2018 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Perforation

(Additions and/or revisions are underlined)

5.6 Expulsion

(Additions and/or revisions are underlined)

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 3.7% was reported, with a rate of 2.1% in nulliparous women and 5.9% in parous women. The majority (76.9%) occur in the first 12 months, with 26.2% occurring in the first three months and 43.1% 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.

5.8 Bleeding Pattern Alterations

(Additions and/or revisions are underlined)

In the LILETTA clinical trial, amenorrhea developed in approximately 19% of LILETTA users by the end of the first year of use, in 27% by the end of the second year of use, in 37% by the end of the third year of use, 37% by the end of the fourth year of use, and 42% by the end of the fifth year of use. In the trial, 2.2% of LILETTA subjects discontinued due to bleeding complaints. Table 2 shows the bleeding and spotting days based on 28-day cycle equivalents.

In the LILETTA clinical trial, 487 of 488 (99.8%) women evaluated experienced menses after LILETTA removal. This excludes twelve women who became pregnant, had a hysterectomy or became menopausal before having a return of their menses.

6 Adverse Reactions

6.1 Clinical Trial Experience

(Additions and/or revisions are underlined)

The data described below reflect exposure of 1,751 generally healthy 16- to 45-year-old women to LILETTA in a large, multi-center contraceptive trial conducted in the US, including 1,401 exposed for 1 year and 496 subjects who completed 5 years of use; 58% were nulliparous (mean age 25.1 + or - 4.3 years) and 42% were parous (mean age 30.3 + or - 6.1 years)…

The clinical trial had no upper or lower weight or BMI limit. Mean BMI of LILETTA subjects was 26.9 kg/m2 (range 15.8 – 61.6 kg/m2); 25.1% had a BMI greater than or equal to 30 kg/m2 of which 5.3% had a BMI greater than or equal to 40 kg/m2. The data cover more than 61,000 28-day cycles of LILETTA exposure. The frequencies of reported adverse drug reactions represent crude incidences.

In the contraceptive trial, 18.8% of LILETTA users discontinued prematurely due to an adverse reaction. The most common adverse reactions leading to discontinuation were expulsion (3.8%) and bleeding complaints (2.2%). The most common adverse reactions leading to discontinuation during the first year of use were expulsion (2.9%) and acne (0.7%). The next most common adverse reactions causing discontinuation were acne (1.4%), dysmenorrhea (1.0%), weight increased (1.0%), menorrhagia (0.9%), mood swings (0.8%), uterine spasm (0.7%), dyspareunia (0.6%) and pelvic pain (0.6%). One woman discontinued the clinical study due to PID and one due to endometritis.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient 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 her that if perforation occurs, LILETTA will have to be located and removed. Surgery may be required. Advise her that delayed detection or removal of LILETTA in case of perforation may result in:

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.

08/03/2017 (SUPPL-4)

Approved Drug Label (PDF)

4 Contraindications

The use of LILETTA is contraindicated when one or more of the following conditions exist:

Additions and/or revisions underlined

Congenital or acquired uterine anomaly, including fibroids, that distorts the uterine cavity and would be incompatible with correct IUS placement
Acute pelvic inflammatory disease (PID) or endometritis or a history of PID unless there has been a subsequent intrauterine pregnancy
Known or suspected breast cancer or other hormone-sensitive cancer, now or in the past …

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Ectopic Pregnancy

… was approximately 0.16 per 100 women-years. The risk of ectopic pregnancy …

5.4 Pelvic Inflammatory Disease or Endometriosis

In the clinical trial with LILETTA, pelvic infection was diagnosed in 0.8% of women. The infection was diagnosed as PID in 0.5% of women and as endometritis in 0.3% of women. One woman diagnosed with PID … The cases of endometritis had onset less than 40 days after LILETTA insertion except for one occurring at 43 months after insertion.

Treatment of PID or endometritis

12 of the 14 women (replaces 1 of the 10 women) who developed PID

5.5 Perforation

… Perforation may reduce contraceptive efficacy and result in pregnancy. This may be associated with severe pain and continued bleeding …

If perforation is suspected the IUS should be removed as soon as possible, surgery may be required … 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 women, compared to 1.0 per 1,000 insertions for non-lactating women.

5.6 Expulsion

… an overall expulsion rate of 3.7% was reported, with a rate of 2.1% in nulliparous women and 5.7% in parous women.

5.8 Bleeding Pattern Alterations

… amenorrhea developed in approximately 19% of LILETTA users by the end of the first year of use, in 27% by the end of the second year of use, in 37% by the end of the third year of use and 41% by the end of the fourth year of use. In the trial, 2.2% of LILETTA subjects discontinued …

In the LILETTA clinical trial, 429 of 439 (97. 7%) women evaluated experienced menses after LILETTA removal. Excluding nine women who became pregnant or had a hysterectomy before having a return of their menses, 429 of 430 (99.8%) had a return of their menses, 99.1% within three months.

5.10 Clinical Considerations for Use and Removal

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:

Exceptionally severe or frequent headache

6 Adverse Reactions

6.1 Clinical Trial Experience

Additions and/or revisions underlined:

… in a large, multi-center contraceptive trial conducted in the US, including 1,409 exposed for 1 year and 837 subjects who completed 4 years of use; 58% were …

… 25.1% had a BMI ? 30 kg/m2 of which 5.3% had a BMI greater than or equal to 40 kg/m2. The data cover more than 59,000 28-day cycles …

In the contraceptive trial, 18.3% of LILETTA users discontinued prematurely due to an adverse reaction. The most common adverse reactions leading to discontinuation were expulsion (3.7%) and bleeding complaints (2.2%). The next most common adverse reactions causing discontinuation were acne (1.4%), dysmenorrhea (1.0%), weight increased (1.0%), mood swings (0.8%), uterine spasm (0.7%) and pelvic pain (0.6%). One woman discontinued the clinical study due to PID and one due to endometritis.

In the clinical trial, serious adverse reactions considered related or possibly related to LILETTA were ectopic pregnancies, ovarian cysts, and IUS perforation …

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

… of clinically recognized pregnancies. Animal reproduction studies have not been conducted with LILETTA. Advise a woman of the potential risks …