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.

NEXPLANON (NDA-021529)

(ETONOGESTREL)

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

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01/16/2026 (SUPPL-27)

Approved Drug Label (PDF)

Boxed Warning

Newly added section:

WARNING: RISK OF COMPLICATIONS DUE TO IMPROPER INSERTION and REMOVAL

Improper insertion of NEXPLANON increases the risk of complications [see Warnings and Precautions (5.1)].
Proper training prior to first use of NEXPLANON can minimize the risk of improper NEXPLANON insertion [see Warnings and Precautions (5.1)].
Because of the risk of complications due to improper insertion and removal NEXPLANON is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the NEXPLANON REMS [see Warnings and Precautions (5.2)].

4 Contraindications

Additions and/or revisions underlined:

NEXPLANON should not be used in women who have

…

Undiagnosed abnormal uterine bleeding

…

5 Warnings and Precautions

5.1 Risk of Complications Due to Improper Insertion and Removal

Subsection title revised

Additions and/or revisions underlined:

…

NEXPLANON is available only through a restricted program under a REMS [see Warnings and Precautions (5.2)].

5.2 NEXPLANON REMS

Newly added subsection:

NEXPLANON is only available through a restricted program under a REMS called NEXPLANON REMS because of the risk of complications due to improper insertion and removal [see Warnings and Precautions (5.1)].

Notable requirements of the NEXPLANON REMS include the following:

Healthcare providers must be certified with the program by enrolling and completing training on the proper insertion and removal of NEXPLANON prior to first use.
Pharmacies must be certified with the program and must only dispense NEXPLANON to certified healthcare providers who dispense NEXPLANON for insertion.
Wholesalers and distributors must be registered with the program and must only distribute to certified pharmacies and certified healthcare providers.

Further information is available at www.NEXPLANONREMS.com and 1-833-697-7367.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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, because clinical trials are conducted under widely varying conditions.

In clinical trials of three years duration involving 942 women who were evaluated for safety, change in menstrual bleeding patterns (irregular menses) was the most common adverse reaction causing discontinuation of use of the non-radiopaque etonogestrel implant (IMPLANON) (11.1% of women).

Adverse reactions that resulted in a rate of discontinuation of greater than or equal to 1% are shown in Table 3.

Table 3: Adverse Reactions Leading to Discontinuation of Treatment in 1% or More of Subjects in 3-Year Clinical Trials of the Non-Radiopaque Etonogestrel Implant (IMPLANON)

…

Table 4: Common Adverse Reactions Reported by greater than or equal to 5% of Subjects in 3-Year Clinical Trials with the Non-Radiopaque Etonogestrel Implant (IMPLANON)

…

In a separate clinical trial to assess contraceptive efficacy and safety of NEXPLANON beyond 3 years, up to 5 years, where a total of 498 women were evaluated for safety, a similar adverse reaction profile was observed as in Years 1 through 3.The most frequently reported adverse reaction >5% related to NEXPLANON was intermenstrual bleeding (5.4%), Changes in menstrual bleeding patterns were the most frequently reported adverse reaction leading to discontinuation occurring in 4.0% of participants.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of NEXPLANON have been established in women of reproductive potential. Safety and effectiveness of NEXPLANON are expected to be the same in postpubertal adolescents as in adult women.

NEXPLANON is not indicated before menarche.

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

PATIENT INFORMATION

Additions and/or revisions underlined:

…

What is NEXPLANON?

NEXPLANON is a hormone-releasing birth control implant for prevention of pregnancy for up to 5 years. The implant is a flexible plastic rod about the size of a matchstick that contains a progestin hormone called etonogestrel. It contains a small amount of barium sulfate (15 mg), so that the implant can be seen by X-ray, an ethylene vinyl acetate (EVA) copolymer (28% vinyl acetate, 43 mg) core, and magnesium stearate (0.1 mg). Your healthcare professional will insert the implant just under the skin of the inner side of your upper arm. You can use a single NEXPLANON implant for up to 5 years. NEXPLANON does not contain estrogen.

…

09/29/2023 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Complications of Insertion/Removal and Broken/Bent Implants

Additions and/or revisions underlined:

…

Broken or Bent Implants

Cases of breakage or bending of implants while inserted within a patient’s arm have been reported. Cases of migration of a broken implant fragment within the arm have also occurred. These cases may be related to external forces, e.g., manipulation of the implant or contact sports. The release rate of etonogestrel may be slightly increased in a broken or bent implant, based on in vitro data. As noted previously, when an implant is removed, it is important to remove it in its entirety [see Dosage and Administration (2.3)].

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Reported complications related to insertion or removal of the etonogestrel implants include vasovagal reactions (e.g., hypotension, dizziness, or syncope), bruising, slight local irritation, pain, itching, fibrosis at the implant site, paresthesia or paresthesia-like events, scarring, and abscesses. Implant expulsions and migrations also have been reported. In some cases, implants have migrated to the chest wall or into the vasculature, including the pulmonary artery. Some cases of implants migrating to the pulmonary artery presented with symptoms of chest pain and/or respiratory disorders (e.g., dyspnea, cough, or hemoptysis); other cases have been reported as asymptomatic. In-patient surgical interventions might be necessary when removing implants associated with complications [see Warnings and Precautions (5.1)].

09/29/2023 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Complications of Insertion/Removal and Broken/Bent Implants

Additions and/or revisions underlined:

…

Broken or Bent Implants

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

09/29/2023 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Complications of Insertion/Removal and Broken/Bent Implants

Additions and/or revisions underlined:

…

Broken or Bent Implants

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

09/24/2020 (SUPPL-19)

4 Contraindications

5.1 Complications of Insertion and Removal

(Additions and/or revisions underlined)

There have been reports of migration of the implant within the arm from the insertion site, which may be related to deep insertion. There also have been postmarketing reports of implants located within the vessels of the arm and the pulmonary artery, which may be related to deep insertions or intravascular insertion. Some cases of implants found within the pulmonary artery were associated with chest pain and/or respiratory disorders (such as dyspnea, cough, or hemoptysis); others were asymptomatic. In cases where the implant has migrated to the pulmonary artery, endovascular or surgical procedures may be needed for removal.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

Adverse Reactions and Events from Postmarketing Study

Nexplanon Observational Risk Assessment Study (NORA)

A postmarketing prospective active surveillance study was conducted among 7,364 patients in the United States to characterize the frequency of insertion-, localization-, and removal-related events.

Implant Insertion

Insertion difficulty or an insertion-related event occurred in 2.6% of the study participants. The overall incidence of incorrect insertion (unrecognized non-insertion, partial insertion, and deep insertion), reported by healthcare professionals was 12.6 per 1,000 insertions (95% CI, 10.2, 15.5). Table 5 summarizes the types and frequencies of these incorrect insertions.

Implant Removal

Implant removal information from both healthcare professionals and patients was collected for 5,159 patients (70% of the study population). Of these patients, data were available from healthcare professionals regarding 4,373 removal procedures. Healthcare professionals reported removal- related difficulties or complications in 1.5% of removal procedures. Table 6 provides a summary.

At the time of implant removal, eighteen implants (0.4% of all localizations or removals) were not palpable by the healthcare professionals. Of these eighteen, eleven were localized and removed, and one was localized but left in situ. Removal was not attempted for six non-palpable implants due to underlying health conditions, administrative problems, or unspecified reasons.

There were no reports of implants having migrated more than a few centimeters from the insertion site and no reports of implants localized at a site other than the arm. No neurovascular injuries were reported by healthcare professionals.

Adverse Reactions Reported by Patients

Table 7 provides a summary of adverse reactions reported by patients at the time of implant insertion and after removal.

In summary, this prospective active surveillance study showed that the frequency of insertion-, localization-, and removal-related events is consistent with results previously reported from clinical trials.

Adverse Reactions from Postmarketing Spontaneous Reports

The following additional adverse reactions have been identified during post-approval use of IMPLANON and NEXPLANON. It is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure because these reactions are reported voluntarily from a population of uncertain size.

Complications related to insertion or removal of the etonogestrel implants reported include: bruising, slight local irritation, pain or itching, fibrosis at the implant site, paresthesia or paresthesia- like events, scarring and abscess. Expulsion or migration of the implant has been reported, including to the chest wall. In some cases, implants have been found within the vasculature, including the pulmonary artery. Some cases of implants found within the pulmonary artery reported chest pain and/or respiratory disorders (such as dyspnea, cough, or hemoptysis); others have been reported as asymptomatic [see Warnings and Precautions (5.1)]. In-patient surgical interventions might be necessary when removing implants associated with complications.

09/24/2020 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Complications of Insertion and Removal

(Additions and/or revisions underlined)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

Adverse Reactions and Events from Postmarketing Study

Nexplanon Observational Risk Assessment Study (NORA)

A postmarketing prospective active surveillance study was conducted among 7,364 patients in the United States to characterize the frequency of insertion-, localization-, and removal-related events.

Implant Insertion

Implant Removal

Adverse Reactions Reported by Patients

Table 7 provides a summary of adverse reactions reported by patients at the time of implant insertion and after removal.

Adverse Reactions from Postmarketing Spontaneous Reports

04/22/2019 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Complications of Insertion and Removal

Additions and/or revisions underlined:

If NEXPLANON is inserted deeply (intramuscular or in the fascia), neural or vascular injury may occur. To help reduce the risk of neural or vascular injury, NEXPLANON should be inserted subdermally just under the skin at the inner side of the non-dominant upper arm overlying the triceps muscle about 8-10 cm (3-4 inches) from the medial epicondyle of the humerus and 3-5 cm (1.25-2 inches) posterior to the sulcus (groove) between the biceps and triceps muscles. This location is intended to avoid the large blood vessels and nerves lying within and surrounding the sulcus. Deep insertions …

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

PATIENT INFORMATION

How is the NEXPLANON implant placed and removed?

The timing of insertion is important. Your healthcare provider may:

Additions and/or revisions underlined:

Schedule the insertion at a specific time of your menstrual cycle (for example, within the first 5 days of your regular menstrual bleeding). If the implant is placed after the fifth day of menses, then you should use an additional contraceptive method (such as a condom) for the first 7 days after insertion.

05/19/2017 (SUPPL-15)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Effects of Other Drugs on Hormonal Contraceptives

(Additions and/or revisions are underlined)

Substances decreasing the plasma concentrations of hormonal contraceptives (HCs) and potentially diminishing the efficacy of HCs:

Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of HCs and potentially diminish the effectiveness of HCs or increase breakthrough bleeding.

Some drugs or herbal products that may decrease the effectiveness of HCs include efavirenz, phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between HCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative non-hormonal method of contraception or a back-up method when enzyme inducers are used with HCs, and to continue back-up non-hormonal contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Substances increasing the plasma concentrations of HCs:

Co-administration of certain HCs and strong or moderate CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase the serum concentrations of progestins, including etonogestrel.

Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) protease inhibitors and non- nucleoside reverse transcriptase inhibitors:

Significant changes (increase or decrease) in the plasma concentrations of progestin have been noted in cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine, efavirenz] or increase [e.g., etravirene]). These changes may be clinically relevant in some cases.

Consult the prescribing information of anti-viral and anti-retroviral concomitant medications to identify potential interactions.

7.2 Effects of Hormonal Contraceptives on Other Drugs

(Additions and/or revisions are underlined)

Hormonal contraceptives may affect the metabolism of other drugs…

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Risk Summary

EXPLANON is contraindicated during pregnancy because there is no need for pregnancy prevention in a woman who is already pregnant. Epidemiologic studies and meta-analyses have not shown an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following maternal exposure to low dose CHCs prior to conception or during early pregnancy. No adverse development outcomes were observed in pregnant rats and rabbits with the administration of etonogestrel during organogenesis at doses of 315 or 781 times the anticipated human dose (60 µg/day).

Animal Data

Teratology studies have been performed in rats and rabbits using oral administration up to 315 and 781 times the human etonogestrel dose (based upon body surface) and revealed no evidence of fetal harm due to etonogestrel exposure.

8.2 Lactation

(Additions and/or revisions are underlined)

Risk Summary

Small amounts of contraceptive steroids and/or metabolites, including etonogestrel are present in human milk. No significant adverse effects have been observed in the production or quality of breast milk, or on the physical and psychomotor development of breastfed infants.

Hormonal contraceptives, including etonogestrel, can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. When possible, advise the nursing mother about both hormonal and non-hormonal contraceptive options, as steroids may not be the initial choice for these patients. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NEXPLANON and any potential adverse effects on the breastfed child from NEXPLANON or from the underlying maternal condition.

Data

The amount of etonogestrel contained within breast milk was measured in 38 lactating women who began using IMPLANON during the fourth to eighth week postpartum. The study evaluated Implanon versus another contraceptive, was not randomized and data were considered observational and exploratory; therefore, comparisons could not be made. Based on the findings of this study, during the first months after insertion of IMPLANON, when maternal blood levels of etonogestrel are highest, about 100 ng of etonogestrel may be ingested by the child per day based on an average daily milk ingestion of 658 mL. Based on daily milk ingestion of 150 mL/kg, the mean daily infant etonogestrel dose one month after insertion of IMPLANON is about 2.2% of the weight-adjusted maternal daily dose, or about 0.2% of the estimated absolute maternal daily dose. Adverse reactions were not observed in breastfed infants exposed to etonogestrel through breast milk. No adverse effects on the production or quality of breast milk were detected.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling

Interaction with Other Medicines

Tell your healthcare provider about all the medicines you take, including prescription and non- prescription medicines, vitamins and herbal supplements. Certain medicines may make IMPLANON less effective, including:

• aprepitant

• Hepatitis C Virus medicines

If you are taking medicines or herbal products that might make IMPLANON less effective, you and your doctor may decide to leave IMPLANON in place; in that case, an additional non- hormonal contraceptive should be used. Because the effect of another medicine on IMPLANON may last up to 28 days after stopping the medicine, it is necessary to use the additional non- hormonal contraceptive for that long.

03/14/2016 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

Complications of Insertion and Removal

There have been reports of migration of the implant within the arm from the insertion site, which may be related to deep insertion. There also have been postmarketing reports of implants located within the vessels of the arm and the pulmonary artery, which may be related to deep insertions or intravascular insertion. In cases where the implant has migrated to the pulmonary artery, endovascular or surgical procedures may be needed for removal.
If at any time the implant cannot be palpated, it should be localized and removal is recommended.
Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged.
Removal of deeply inserted implants should be conducted with caution in order to prevent injury to deeper neural or vascular structures in the arm and be performed by healthcare providers familiar with the anatomy of the arm. If the implant is located in the chest, healthcare providers familiar with the anatomy of the chest should be consulted. Failure to remove the implant may result in continued effects of etonogestrel, such as compromised fertility, ectopic pregnancy, or persistence or occurrence of a drug related adverse event.

6 Adverse Reactions

Postmarketing Experience

Expulsion or migration of the implant have been reported, including to the chest wall. In some cases, implants have been found within the vasculature, including the pulmonary artery. Some cases of implants found within the pulmonary artery reported chest pain and/or dyspnea; others have been reported as asymptomatic. Surgical intervention might be necessary when removing the implant.