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.

KYLEENA (NDA-208224)

(LEVONORGESTREL)

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

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05/04/2023 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition and/or revisions to Table 5: Uterine Perforation rates for LNG IUS, by Breastfeeding Stats and Postpartum Interval; please refer to label for complete information

01/10/2022 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Perforation

Additions and/or revisions underlined:

Perforation (total or partial, including penetration/embedment of Kyleena in the uterine wall or cervix) may occur most often during insertion, although the perforation may not be detected until sometime later. The incidence of perforation during clinical trials was < 0.1%.

The risk of uterine perforation is increased in women who have recently given birth, and in women who are breastfeeding at the time of insertion. In a large postmarketing safety study conducted in the US, the risk of uterine perforation was highest when insertion occurred within less than or equal to 6 weeks postpartum, and also higher with breastfeeding at the time of insertion [see Adverse Reactions (6.2)].

The risk of perforation may be increased if Kyleena is inserted when the uterus is fixed, retroverted or not completely involuted.

If perforation occurs, locate and remove Kyleena. Surgery may be required. Delayed detection or removal of Kyleena 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 addition, perforation may reduce contraceptive efficacy and result in pregnancy.

5.6 Expulsion

Additions and/or revisions underlined:

Partial or complete expulsion of Kyleena may occur resulting in the loss of efficacy. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed ... Consider further diagnostic imaging, such as x-ray, if expulsion is suspected based on ultrasound [see Warnings and Precautions (5.10)]. In clinical trials, a 5-year expulsion rate of 3.5% (59 out of 1,690 subjects) was reported.

The risk of expulsion is increased with insertions immediately after delivery and appears to be increased with insertion after second-trimester abortion based on limited data. In a large postmarketing safety study conducted in the US, the risk of expulsion was lower with breastfeeding status [see Adverse Reactions (6.2)].

Remove a partially expelled Kyleena …

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Adverse Reactions from Postmarketing Spontaneous Reports

The following adverse reactions have been identified during post-approval use of LNG-releasing IUSs …

Newly added information:
Reported Adverse Reactions from Postmarketing Studies

Assessment of Perforation and Expulsion of Intrauterine Devices (APEX IUD) Study

APEX IUD was a large US retrospective cohort study to assess the impact of breastfeeding and timing of postpartum IUD insertion on uterine perforation and IUD expulsion. The analyses included a total of 326,658 insertions, 30% (97,824 insertions) of which were performed in women with a delivery in the previous 12 months. For insertions performed in women who had delivered less than or equal to 52 weeks before IUD insertion, the majority of postpartum insertions, 57.3% (56,047 insertions) occurred between 6 and 14 weeks postpartum. Breastfeeding data were available in 94,817 insertions performed in women 52 weeks or less after delivery.

The study results indicated that the risk of uterine perforation was highest in women with IUD insertion less than or equal to 6 weeks postpartum. Immediate postpartum insertion (0–3 days) findings are limited due to the relatively small number of insertions occurring within this time interval. Women who were breastfeeding at the time of insertion were at 33% higher risk of perforation (adjusted hazard ratio [HR]=1.33, 95% confidence interval [CI]: 1.07–1.64) compared to women who were not breastfeeding at the time of insertion. Progressively lower risk of uterine perforation was observed in postpartum time windows beyond 6 weeks, in both breastfeeding and not breastfeeding women. Table 5 presents the uterine perforation rates for LNG IUS stratified by breastfeeding status and postpartum interval.

Table 5: Uterine Perforation rates for LNG IUS, by Breastfeeding Status and Postpartum Interval (Newly added table; please refer to label for complete information).

Risk of expulsion was variable over the postpartum intervals through 52 weeks. Women who were breastfeeding were at 28% lower risk of IUD expulsion (adjusted HR=0.72, 95% CI: 0.64-0.80) compared to women who were not breastfeeding at time of insertion. Table 6 presents the IUD expulsion rates for LNG IUS stratified by breastfeeding status and postpartum interval.

Table 6: Expulsion Rates for LNG IUS, by Breastfeeding Status and Postpartum Interval

(Newly added table; please refer to label for complete information).

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

PATIENT INFORMATION

Additions and/or revisions underlined:
How is Kyleena placed?

Kyleena is placed by your healthcare provider during an in-office visit or immediately after giving

birth.

What are the possible side effects of Kyleena?

Kyleena can cause serious side effects including:

Perforation. The risk of perforation is increased if Kyleena is inserted while you are breastfeeding, or if you have recently given birth.
Expulsion. If you think that Kyleena has come out, avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide) and call your healthcare provider. The risk of expulsion is increased with insertion right after delivery or second-trimester abortion.

04/13/2021 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risks with Intrauterine Pregnancy

Additions underlined

…

Continuation of pregnancy

If a woman becomes pregnant with Kyleena in place and if Kyleena cannot be removed or the woman chooses not to have it removed, warn her that failure to remove Kyleena increases the risk of miscarriage, sepsis, premature labor and premature delivery. Advise her of isolated reports of virilization of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place [see Use in Specific Populations (8.1)]. Follow her pregnancy closely and advise her to report immediately any symptom that suggests complications of the pregnancy.

5.6 Expulsion

Additions underlined

Partial or complete expulsion of Kyleena may occur resulting in the loss of contraceptive protection. Expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. Kyleena typically decreases menstrual bleeding over time; therefore, an increase of menstrual bleeding may be indicative of an expulsion. Consider further diagnostic imaging, such as x-ray, if expulsion is suspected based on ultrasound [see Warnings and Precautions (5.10)]. The risk of expulsion may be increased when the uterus is not completely involuted. In clinical trials, a 5-year expulsion rate of 3.5% (59 out of 1,690 subjects) was reported.

…

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined

…

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 Kyleena.

8.3 Females and Males of Reproductive Potential

New subsection added

Return to Fertility After Discontinuing Kyleena

About 71% of 163 women who desired pregnancy after study discontinuation and provided follow-up information, conceived within 12 months after removal of Kyleena.

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

PATIENT COUNSELING INFORMATION

Additions underlined

…

Risks of Intrauterine Pregnancy: Advise the patient to contact her healthcare provider if she thinks she might be pregnant. Inform the patient about the risks of intrauterine pregnancy while using Kyleena, including the risks of leaving Kyleena in place and the risks of removing Kyleena or probing of the uterus. If Kyleena cannot be removed in a pregnant patient, advise her to report immediately any symptom that suggests complications of the pregnancy. Advise her of isolated reports of virilization of the female fetus following local exposure to LNG during pregnancy with an LNG IUS in place. [See Warnings and Precautions (5.2) and Use in Special Populations (8.1).]

…

Perforation and Expulsion: Advise the patient that the IUS may be expelled from or perforate the uterus and instruct her on how she can check that the threads still protrude from the cervix. Inform her that excessive pain or vaginal bleeding during Kyleena placement, worsening pain or bleeding after placement, or the inability to feel Kyleena strings may occur with Kyleena perforation and expulsion. Caution her not to pull on the threads and displace Kyleena. Inform her that there is no contraceptive protection if Kyleena is displaced or expelled. Instruct the patient to contact her healthcare provider if she cannot feel the threads and to avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide) until the location of Kyleena has been confirmed. Advise her that if perforation occurs, Kyleena will have to be located and removed; surgery may be required. [See Warnings and Precautions (5.5, 5.6, 5.10).]

…

PATIENT INFORMATION

Additions underlined

…

Do not use Kyleena if you:

…

can get infections easily. For example, if you:

have multiple sexual partners or your partner has multiple sexual partners
have problems with your immune system
use or abuse intravenous drugs
…
Before having Kyleena placed, tell your healthcare provider about all of your medical conditions including if you:
…

have AIDS, HIV, or any other sexually transmitted infection

…

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

…

Can I use tampons or menstrual cups with Kyleena?

Yes, tampons or menstrual cups may be used with Kyleena. Change tampons or menstrual cups with care to avoid pulling the threads of Kyleena. If you think you may have pulled Kyleena out of place, avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide), and contact your healthcare provider.

…

What if I become pregnant while using Kyleena?

… If Kyleena cannot be removed, talk with your healthcare provider about the benefits and risks of continuing the pregnancyand possible effects of the hormone on your unborn baby.

…

What are the possible side effects of Kyleena?

Kyleena can cause serious side effects including:

…

Expulsion. Kyleena may come out by itself. This is called expulsion. Expulsion occurs in about 4 out of 100 women. Excessive pain or vaginal bleeding during placement of Kyleena, pain or bleeding that gets worse after placement, or not being able to feel the threads may happen with expulsion. You may become pregnant if Kyleena comes out. If you think that Kyleena has come out, avoid intercourse or use a non-hormonal back-up birth control (such as condoms or spermicide) and call your healthcare provider.

…

03/01/2018 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Perforation

Additions and/or revisions underlined:

… Delay Kyleena insertion a minimum of six weeks or until involution is complete following a delivery or a second trimester abortion.

Clinical trials with Kyleena excluded breast-feeding women. A large postmarketing safety study conducted in Europe over a 1-year observational period reported that lactation at the time of insertion of an IUD/IUS was associated with an increased risk of perforation. For users of another LNG-releasing 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

Delay Kyleena insertion a minimum of six weeks or until uterine involution is complete following a delivery or a second trimester abortion. Remove a partially expelled Kyleena. If expulsion has occurred, a new Kyleena can be inserted any time the provider can be reasonably certain the woman is not pregnant.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

… If a woman becomes pregnant with Kyleena in place, the likelihood of ectopic pregnancy is increased and there is an increased risk of miscarriage, sepsis, premature labor, and premature delivery. Remove Kyleena, if possible, if pregnancy occurs in a woman using Kyleena. If Kyleena cannot be removed, follow the pregnancy closely.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Risks of Intrauterine Pregnancy: … and the risks of removing Kyleena or probing of the uterus. If Kyleena cannot be removed in a pregnant patient, advise her to report immediately any symptom that suggests complications of the pregnancy.