Etonogestrel

NEXPLANON ® is indicated for prevention of pregnancy in women of reproductive potential for up to 5 years. NEXPLANON is a progestin indicated for prevention of pregnancy in women of reproductive potential for up to 5 years. ( 1 )

Single, white/off-white, soft, radiopaque, flexible, ethylene vinyl acetate (EVA) copolymer implant, 4 cm in length and 2 mm in diameter containing 68 mg etonogestrel, 15 mg of barium sulfate, and 0.1 mg of magnesium stearate. NEXPLANON consists of a single, radiopaque, rod-shaped implant, containing 68 mg etonogestrel, pre-loaded in the needle of a disposable applicator. ( 3 )

NEXPLANON should not be used in women who have Known or suspected pregnancy Current or past history of thrombosis or thromboembolic disorders Liver tumors, benign or malignant, or active liver disease Undiagnosed abnormal uterine bleeding Known or suspected breast cancer, personal history of breast cancer, or other progestin-sensitive cancer, now or in the past Allergic reaction to any of the components of NEXPLANON [see Adverse Reactions (6) ] Known or suspected pregnancy. ( 4 ) Current or past history of thrombosis or thromboembolic disorders. ( 4 , 5.5 ) Liver tumors, benign or malignant, or active liver disease. ( 4 , 5.8 ) Undiagnosed abnormal uterine bleeding. ( 4 , 5.3 ) Known or suspected breast cancer, personal history of breast cancer, or other progestin-sensitive cancer, now or in the past. ( 4 , 5.7 ) Allergic reaction to any of the components of NEXPLANON. ( 4 , 6 )

The following information is based on experience with the etonogestrel implants (IMPLANON and/or NEXPLANON), other progestin-only contraceptives, or experience with combination (estrogen plus progestin) oral contraceptives. Insertion and removal complications: Pain, paresthesia, bleeding, hematoma, scarring, infection, or migration to vasculature, including pulmonary vessels, may occur. Symptoms associated with implants in pulmonary vessels include chest pain, dyspnea, cough, or hemoptysis. Surgical interventions may be necessary to remove implants. ( 5.1 ) Menstrual bleeding pattern: Counsel women regarding changes in bleeding frequency, intensity, or duration. ( 5.3 ) Ectopic pregnancies: Be alert to the possibility of an ectopic pregnancy in women using NEXPLANON who become pregnant or complain of lower abdominal pain. ( 5.4 ) Thrombotic and other vascular events: The NEXPLANON implant should be removed in the event of a thrombosis. ( 5.5 ) Liver disease: Remove the NEXPLANON implant if jaundice occurs. ( 5.8 ) Elevated blood pressure: The NEXPLANON implant should be removed if blood pressure rises significantly and becomes uncontrolled. ( 5.10 ) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women using NEXPLANON. ( 5.12 )

5.1 Risk of Complications Due to Improper Insertion and Removal Complications of Insertion and Removal NEXPLANON should be inserted subdermally so that it will be palpable after insertion, and this should be confirmed by palpation immediately after insertion. Failure to insert NEXPLANON properly may go unnoticed unless it is palpated immediately after insertion. Undetected failure to insert the implant may lead to an unintended pregnancy. Complications related to insertion and removal procedures may occur, e.g., pain, paresthesia, bleeding, hematoma, scarring, or infection. If NEXPLANON is inserted deeply (intramuscular or intrafascial), 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 (below) the sulcus (groove) between the biceps and triceps muscles. This location is intended to avoid the large nerves and blood vessels lying within and surrounding the sulcus. Deep insertions of NEXPLANON have been associated with paresthesia (due to neural injury), migration of the implant (due to intramuscular or fascial insertion), and intravascular insertion. If infection develops at the insertion site, start suitable treatment. If the infection persists, the implant should be removed. Incomplete insertions or infections may lead to expulsion. Reports of implant migration within the arm may have been related to deep insertion. Postmarketing reports of implants located within the vessels of the arm and the pulmonary artery also may have been related to deep insertions or intravascular insertions. 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. Implant removal may be difficult or impossible if the implant is not inserted correctly, is inserted too deeply, not palpable, encased in fibrous tissue, or has migrated. If at any time the implant cannot be palpated, it should be localized, and removal is recommended. When an implant is removed, it is important to remove it in its entirety [see Dosage and Administration (2.3) ] . 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 professionals familiar with the anatomy of the arm. If the implant is located in the chest, healthcare professionals 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. 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) ] . NEXPLANON is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ]. 5.2 NEXPLANON REMS 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.

5.3 Changes in Menstrual Bleeding Patterns After starting NEXPLANON, women are likely to have a change from their normal menstrual bleeding pattern. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration. In clinical trials of the non-radiopaque etonogestrel implant (IMPLANON), bleeding patterns ranged from amenorrhea (1 in 5 women) to frequent and/or prolonged bleeding (1 in 5 women). The bleeding pattern experienced during the first three months of NEXPLANON use is broadly predictive of the future bleeding pattern for many women. Women should be counseled regarding the bleeding pattern changes they may experience so that they know what to expect. Abnormal bleeding should be evaluated as needed to exclude pathologic conditions or pregnancy. In clinical studies of the non-radiopaque etonogestrel implant, reports of changes in bleeding pattern were the most common reason for stopping treatment (11.1%). Irregular bleeding (10.8%) was the single most common reason women stopped treatment, while amenorrhea (0.3%) was cited less frequently. In these studies, women had an average of 17.7 days of bleeding or spotting every 90 days (based on 3,315 intervals of 90 days recorded by 780 patients). The percentages of patients having 0, 1-7, 8-21, or >21 days of spotting or bleeding over a 90-day interval while using the non-radiopaque etonogestrel implant are shown in Table 1 . Table 1: Bleeding or Spotting: Incidence and Duration Over a 90-Day Interval While Using the Non-Radiopaque Etonogestrel Implant (IMPLANON) Total Days of Bleeding or Spotting Percentage of Patients Treatment Days 91-180 (N = 745) Treatment Days 271-360 (N = 657) Treatment Days 631-720 (N = 547) 0 Days 19% 24% 17% 1-7 Days 15% 13% 12% 8-21 Days 30% 30% 37% >21 Days 35% 33% 35% Bleeding patterns observed with use of the non-radiopaque etonogestrel implant for up to 2 years, and the proportion of 90-day intervals with these bleeding patterns, are summarized in Table 2 . […]

The following adverse reactions reported with the use of hormonal contraception are discussed elsewhere in the labeling: Changes in Menstrual Bleeding Patterns [see Warnings and Precautions (5.3) ] Ectopic Pregnancies [see Warnings and Precautions (5.4) ] Thrombotic and Other Vascular Events [see Warnings and Precautions (5.5) ] Liver Disease [see Warnings and Precautions (5.8) ] Most common (≥10%) adverse reactions reported in clinical trials were change in menstrual bleeding pattern, headache, vaginitis, weight increase, acne, breast pain, abdominal pain, and pharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Organon USA LLC, a subsidiary of Organon & Co., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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 ≥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) Adverse Reactions All Studies N = 942 Bleeding Irregularities Includes "frequent", "heavy", "prolonged", "spotting", and other patterns of bleeding irregularity. 11.1% Emotional Lability Among US subjects (N=330), 6.1% experienced emotional lability that led to discontinuation. 2.3% Weight Increase 2.3% Headache 1.6% Acne 1.3% Depression Among US subjects (N=330), 2.4% experienced depression that led to discontinuation. 1.0% Other adverse reactions that were reported by at least 5% of subjects in the non-radiopaque etonogestrel implant clinical trials are listed in Table 4 . Table 4: Common Adverse Reactions Reported by ≥5% of Subjects in 3-Year Clinical Trials with the Non-Radiopaque Etonogestrel Implant (IMPLANON) Adverse Reactions All Studies N = 942 Headache 24.9% Vaginitis 14.5% Weight increase 13.7% Acne 13.5% Breast pain 12.8% Abdominal pain 10.9% Pharyngitis 10.5% Leukorrhea 9.6% Influenza-like symptoms 7.6% Dizziness 7.2% Dysmenorrhea 7.2% Back pain 6.8% Emotional lability 6.5% Nausea 6.4% Pain 5.6% Nervousness 5.6% Depression 5.5% Hypersensitivity 5.4% Insertion site pain 5.2% In a clinical trial of NEXPLANON, in which investigators were asked to examine the implant site after insertion, implant site reactions were reported in 8.6% of women. Erythema was the most frequent implant site complication, reported during or shortly after insertion, occurring in 3.3% of subjects. Additionally, hematoma (3.0%), bruising (2.0%), pain (1.0%), and swelling (0.7%) were reported. 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.

6.2 Postmarketing Experience 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. Table 5: Incorrect Insertion Types and Incidence Reported by Healthcare Professionals Type of Incorrect Insertion Event Number of Events Total Insertion Procedures = 7,364 Incidence per 1,000 Insertions (95% CI) (Initially) Unrecognized Non-insertions 1 0.1 (0.0-0.8) Partial Insertions 27 3.7 (2.4-5.3) Deep Insertions 65 8.8 (6.8-11.2) Injury to nerve or blood vessel 1 0.1 (0.0-0.8) Implant located within muscle 2 0.3 (0.0-1.0) Implant located adjacent to fascial tissue 56 7.6 (5.8-9.9) Implant not palpable 6 0.8 (0.3-1.8) 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. Table 6: Removal-related Events Reported by Healthcare Professionals Removal Related Events Number of Events Total Removal Procedures: N= 4,373 Incidence per 1,000 Removals (95% CI) Any Event Limited to one event per removal procedure 60 13.7 (10.5-17.6) Encased in Fibrotic Tissue 29 6.6 (4.4-9.5) Implant Too Deep 11 2.5 (1.3-4.5) Implant Migrated Only local migrations within the arm reported 6 1.4 (0.5-3.0) Multiple Attempts Required 13 3.0 (1.6-5.1) Other Other included fragmented or bent implants, patient-related issues, wound care required, two incisions required, and difficulty identifying end of device. 14 3.2 (1.8-5.4) 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. Table 7: Adverse Reactions Reported by Patients at Implant Insertion and after Removal Patient Reported Adverse Reactions At Insertion After Removal N Total Insertion Procedures: N = 7,364 Incidence per 1000 insertions (95% CI) N Incidence per 1000 insertions (95% CI) Any Event Limited to one event per woman 49 6.7 (4.9-8.8) 42 Based on 3,447 questionnaires 5.7 (4.1-7.7) Pins and Needles/Numbness (arm/hand/fingers) 17 2.3 (1.4-3.7) 24 3.3 (2.1-4.9) Severe Pain 10 1.4 (0.7-2.5) 11 1.5 (0.8-2.7) Altered Strength/Movement 3 0.4 (0.1-1.2) 8 1.1 (0.5-2.1) Injury to Blood Vessels or Blood Clots in Arm No blood clots were observed during the study 2 0.3 (0-1.0) — — Other “Other” included localized or insertion site pain, soreness, tenderness, dermatological changes, itching, bruising, and infection, local migrations within the arm, and physical damage to the implant (e.g., fractured or bent implant). 22 3.0 (1.9-4.5) 18 2.4 (1.5-3.9) 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. […]

Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Drugs or herbal products that induce certain enzymes, such as CYP3A4, may decrease the effectiveness of progestin hormonal contraceptives or increase breakthrough bleeding. ( 7.1 )

7.1 Effects of Other Drugs on Hormonal Contraceptives 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) 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] or increase [e.g., indinavir, ritonavir and ritonavir-boosted protease inhibitors]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine, efavirenz] or increase [e.g., etravirine]). 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 Hormonal contraceptives may affect the metabolism of other drugs. Consequently, plasma concentrations may either increase (for example, cyclosporine) or decrease (for example, lamotrigine). Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

Pregnancy: Discontinue if maintaining a pregnancy. ( 8.1 )

8.1 Pregnancy Risk Summary NEXPLANON is contraindicated during pregnancy because there is no need for pregnancy prevention in a woman who is already pregnant [see Contraindications (4) ] . 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) (see Data ) . NEXPLANON should be removed if maintaining a pregnancy. Data 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 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 (see Data ) . 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.

8.4 Pediatric Use 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.

8.5 Geriatric Use This product has not been studied in women over 65 years of age and is not indicated in this population.

8.6 Hepatic Impairment No studies were conducted to evaluate the effect of hepatic disease on the disposition of NEXPLANON. The use of NEXPLANON in women with active liver disease is contraindicated [see Contraindications (4) ] .

The contraceptive effect of NEXPLANON is achieved by suppression of ovulation, increased viscosity of the cervical mucus, and alterations in the endometrium.