Nexplanon

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION The efficacy of NEXPLANON does not depend on daily, weekly, or monthly administration. All healthcare professionals should receive instruction and training prior to performing insertion and/or removal of NEXPLANON. A single NEXPLANON implant is inserted subdermally just under the skin at the inner side of the non-dominant upper arm. The insertion site is 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 blood vessels and nerves lying within and surrounding the sulcus (see Figures 2a , 2b and 2c ). Inserting an implant more deeply than subdermally (a deep insertion) may preclude palpation and localization, making removal difficult or impossible [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . NEXPLANON must be inserted by the expiration date stated on the packaging. NEXPLANON is a long-acting (up to 5 years), reversible, hormonal contraceptive method. The implant must be removed by the end of the fifth year and may be replaced by a new implant at the time of removal, if continued contraceptive protection is desired. Insert one NEXPLANON subdermally just under the skin at the inner side of the non-dominant upper arm. NEXPLANON must be removed no later than by the end of the fifth year. ( 2 ) 2.1 Initiating Contraception with NEXPLANON IMPORTANT: Rule out pregnancy before inserting the implant. Timing of insertion depends on the woman's recent contraceptive history, as follows: • No preceding hormonal contraceptive use in the past month NEXPLANON should be inserted between Day 1 (first day of menstrual bleeding) and Day 5 of the menstrual cycle, even if the woman is still bleeding. If inserted as recommended, back-up contraception is not necessary. If deviating from the recommended timing of insertion, the woman should be advised to use a barrier method until 7 days after insertion. If intercourse has already occurred, pregnancy should be excluded. • Switching contraceptive method to NEXPLANON Combination hormonal contraceptives: NEXPLANON should preferably be inserted on the day after the last active tablet of the previous combined oral contraceptive or on the day of removal of the vaginal ring or transdermal patch. At the latest, NEXPLANON should be inserted on the day following the usual tablet-free, ring-free, patch-free or placebo tablet interval of the previous combined hormonal contraceptive. If inserted as recommended, back-up contraception is not necessary. If deviating from the recommended timing of insertion, the woman should be advised to use a barrier method until 7 days after insertion. If intercourse has already occurred, pregnancy should be excluded. Progestin-only contraceptives: There are several types of progestin-only methods. NEXPLANON should be inserted as follows: Injectable Contraceptives: Insert NEXPLANON on the day the next injection is due. Minipill: A woman may switch to NEXPLANON on any day of the month. NEXPLANON should be inserted within 24 hours after taking the last tablet. Contraceptive implant or intrauterine system (IUS): Insert NEXPLANON on the same day the previous contraceptive implant or IUS is removed. If inserted as recommended, back-up contraception is not necessary. If deviating from the recommended timing of insertion, the woman should be advised to use a barrier method until 7 days after insertion. If intercourse has already occurred, pregnancy should be excluded. • Following abortion or miscarriage First Trimester: NEXPLANON should be inserted within 5 days following a first trimester abortion or miscarriage. Second Trimester: Insert NEXPLANON between 21 to 28 days following second trimester abortion or miscarriage. If inserted as recommended, back-up contraception is not necessary. If deviating from the recommended timing of insert…

5 WARNINGS AND PRECAUTIONS 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 de…

4 CONTRAINDICATIONS 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 )

7 DRUG INTERACTIONS 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)/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., 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.

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.

6 ADVERSE REACTIONS 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…