Nexplanon

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 (5.2) ] Ectopic Pregnancies [see Warnings and Precautions (5.3) ] Thrombotic and Other Vascular Events [see Warnings and Precautions (5.4) ] Liver Disease [see Warnings and Precautions (5.7) ] 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 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 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 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. 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. 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. Gastrointestinal disorders: constipation, diarrhea, flatulence, vomiting. General disorders and administration site conditions: edema, fatigue, implant site reaction, pyrexia. Immune system disorders: anaphylactic reactions. Infections and infestations: rhinitis, urinary tract infection. Investigations: clinically relevant rise in blood pressure, weight decreased. Metabolism and nutrition disorders: increased appetite. Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, myalgia. Nervous system disorders: convulsions, migraine, somnolence. Pregnancy, puerperium and perinatal conditions: ectopic pregnancy. Psychiatric disorders: anxiety, insomnia, libido decreased. Renal and urinary disorders: dysuria. Reproductive system and breast disorders: breast discharge, breast enlargement, ovarian cyst, pruritus genital, vulvovaginal discomfort. Skin and subcutaneous tissue disorders: angioedema, aggravation of angioedema and/or aggravation of hereditary angioedema, alopecia, chloasma, hypertrichosis, pruritus, rash, seborrhea, urticaria. Vascular disorders: hot flush. 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) ] .

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 genital 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 , 5.4 ) Liver tumors, benign or malignant, or active liver disease. ( 4 , 5.7 ) Undiagnosed abnormal genital bleeding. ( 4 , 5.2 ) Known or suspected breast cancer, personal history of breast cancer, or other progestin-sensitive cancer, now or in the past. ( 4 , 5.6 ) Allergic reaction to any of the components of NEXPLANON. ( 4 , 6 )

11 DESCRIPTION NEXPLANON is a radiopaque, progestin-only, soft, flexible implant preloaded in a sterile, disposable applicator for subdermal use. The implant is white/off-white, non-biodegradable and 4 cm in length with a diameter of 2 mm (see Figure 19 ). Each implant consists of an ethylene vinyl acetate (EVA) copolymer (28% vinyl acetate, 43 mg) core, containing 68 mg of the synthetic progestin etonogestrel, barium sulfate ((15 mg), radiopaque ingredient), and magnesium stearate (0.1 mg), surrounded by an EVA copolymer skin. Once inserted subdermally, the release rate is 60-70 mcg/day in week 5-6 and decreases to approximately 35-45 mcg/day at the end of the first year, to approximately 30-40 mcg/day at the end of the second year, and then to approximately 25-30 mcg/day at the end of the third year. NEXPLANON is a progestin-only contraceptive and does not contain estrogen. NEXPLANON does not contain latex. Figure 19 (Not to scale) Etonogestrel [13-Ethyl-17-hydroxy-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-3-one], structurally derived from 19-nortestosterone, is the synthetic biologically active metabolite of the synthetic progestin desogestrel. It has a molecular weight of 324.46 and the following structural formula ( Figure 20 ). Figure 20 Figure 19 Figure 20

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 3 years), reversible, hormonal contraceptive method. The implant must be removed by the end of the third 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 third 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 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. • Postpartum Not Breastfeeding: NEXPLANON should be inserted between 21 to 28 days postpartum. 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. Breastfeeding: NEXPLANON should not be inserted until after the fourth postpartum week. The woman should be advised to use a barrier method until 7 days after insertion. If intercourse has already occurred, pregnancy should be excluded. 2.2 Insertion of NEXPLANON The basis for successful use and subsequent removal of NEXPLANON is a correct and carefully performed subdermal insertion of the single, rod-shaped implant in accordance with the instructions . Both the healthcare professional and the woman should be able to feel the implant under the skin after placement. All healthcare professionals performing insertions and/or removals of NEXPLANON should receive instructions and training prior to inserting or removing the implant. Preparation Before inserting NEXPLANON, carefully read the instructions for insertion as well as the full prescribing information. If you are unsure of the necessary steps to safely insert and/or remove NEXPLANON, do not attempt the procedure. Call the Organon Service Center at 1-844-674-3200 if you have any questions. Videos demonstrating insertion and removal are available online for trained healthcare professionals (www.nexplanontraining.com). Before insertion of NEXPLANON, the healthcare professional should confirm that: The woman is not pregnant and has no other contraindication for the use of NEXPLANON [see Contraindications (4) ] . The woman has had a medical history and physical examination, including a gynecologic examination, performed. The woman understands the benefits and risks of NEXPLANON. The woman has received a copy of the Patient Labeling included in packaging. The woman does not have allergies to the antiseptic and anesthetic to be used during insertion. Insert NEXPLANON under aseptic conditions. The following equipment is needed for the implant insertion: An examination table for the woman to lie on Sterile surgical drapes, sterile gloves, antiseptic solution, surgical marker Local anesthetic, needles, and syringe Sterile gauze, adhesive bandage, pressure bandage Insertion Procedure To help make sure the implant is inserted just under the skin, the healthcare professionals should be positioned to see the advancement of the needle by viewing the applicator from the side and not from above the arm. From the side view, the insertion site and the movement of the needle just under the skin can be clearly visualized. For illustrative purposes, Figures depict the left inner arm. Step 1. Have the woman lie on her back on the examination table with her non-dominant arm flexed at the elbow and externally rotated so that her hand is underneath her head (or as close as possible) ( Figure 1 ). Figure 1 Step 2. Identify the insertion site, which is 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 (Figures 2a, 2b and 2c). This location is intended to avoid the large blood vessels and nerves lying within and surrounding the sulcus. If it is not possible to insert the implant in this location (e.g., in women with thin arms), it should be inserted as far posterior from the sulcus as possible. [See Warnings and Precautions (5.1) .] Step 3. Make two marks with a surgical marker: first, mark the spot where the etonogestrel implant will be inserted, and second, mark a spot at 5 centimeters (2 inches) proximal (toward the shoulder) to the first mark ( Figure 2a and 2b ). This second mark (guiding mark) will later serve as a direction guide during insertion. Figure 2a P – Proximal (toward the shoulder) D – Distal (toward the elbow) Figure 2b Figure 2c: Cross section of the upper left arm, as viewed from the elbow Medial (inner side of the arm) Lateral (outer side of the arm) Step 4. After marking the arm, confirm the site is in the correct location on the inner side of the arm. Step 5. Clean the skin from the insertion site to the guiding mark with an antiseptic solution. Step 6. Anesthetize the insertion area (for example, with anesthetic spray or by injecting 2 mL of 1% lidocaine just under the skin along the planned insertion tunnel). Step 7. Remove the sterile preloaded disposable NEXPLANON applicator containing the implant from its blister packaging. Prior to use, visually inspect the packaging for breaches of integrity or damage (e.g., torn, punctured, etc.). If the packaging has any visual damage that could compromise sterility, do not use the product. Step 8. Hold the applicator just above the needle at the textured surface area. Remove the transparent protection cap by sliding it horizontally in the direction of the arrow away from the needle ( Figure 3 ). If the cap does not come off easily, the applicator should not be used. You should see the white colored implant by looking into the tip of the needle. Do not touch the purple slider until you have fully inserted the needle subdermally, as doing so will retract the needle and prematurely release the implant from the applicator. Step 9. If the purple slider is released prematurely, restart the procedure with a new applicator. Figure 3 Step 10. With your free hand, stretch the skin around the insertion site towards the elbow ( Figure 4 ). Figure 4 Step 11. The implant should be inserted subdermally just under the skin [see Warnings and Precautions (5.1) ] . To help make sure the implant is inserted just under the skin, you should position yourself to see the advancement of the needle by viewing the applicator from the side and not from above the arm. From the side view (see Figure 6 ), you can clearly see the insertion site and the movement of the needle just under the skin. Step 12. Puncture the skin with the tip of the needle slightly angled less than 30° ( Figure 5a ). Figure 5a Step 13. Insert the needle until the bevel (slanted opening of the tip) is just under the skin (and no further) ( Figure 5b ). If you inserted the needle deeper than the bevel, withdraw the needle until only the bevel is beneath the skin. Figure 5b Step 14. Lower the applicator to a nearly horizontal position. To facilitate subdermal placement, lift the skin with the needle while sliding the needle to its full length ( Figure 6 ). You may feel slight resistance but do not exert excessive force. If the needle is not inserted to its full length, the implant will not be inserted properly. If the needle tip emerges from the skin before needle insertion is complete, the needle should be pulled back and be readjusted to subdermal position before completing the insertion procedure. Figure 6 Step 15. Keep the applicator in the same position with the needle inserted to its full length ( Figure 7 ). If needed, you may use your free hand to stabilize the applicator. Unlock the purple slider by pushing it slightly down ( Figure 8a ). Move the slider fully back until it stops. Do not move the applicator while moving the purple slider ( Figure 8b ). The implant is now in its final subdermal position, and the needle is locked inside the body of the applicator. The applicator can now be removed ( Figure 8c ). Figure 7 Figure 8a Figure 8b Figure 8c If the applicator is not kept in the same position during this procedure or if the purple slider is not moved fully back until it stops, the implant will not be inserted properly and may protrude from the insertion site. If the implant is protruding from the insertion site, remove the implant and perform a new procedure at the same insertion site using a new applicator. Do not push the protruding implant back into the incision. Step 16. Apply a small adhesive bandage over the insertion site. Step 17. Always verify the presence of the implant in the woman's arm immediately after insertion by palpation. By palpating both ends of the implant, you should be able to confirm the presence of the 4 cm rod ( Figure 9 ). See " If the rod is not palpable after insertion " below. Figure 9 Step 18. Request that the woman palpate the implant. Step 19. Apply a pressure bandage with sterile gauze to minimize bruising. The woman may remove the pressure bandage in 24 hours and the small adhesive bandage over the insertion site after 3 to 5 days. Step 20. Complete the PATIENT CHART LABEL and affix it to the woman's medical record. Step 21. The applicator is for single use only and should be disposed in accordance with the Center for Disease Control and Prevention guidelines for handling of hazardous waste. If the rod is not palpable after insertion: If you cannot feel the implant or are in doubt of its presence, the implant may not have been inserted or it may have been inserted deeply: Check the applicator. The needle should be fully retracted and only the purple tip of the obturator should be visible. Use other methods to confirm the presence of the implant. Given the radiopaque nature of the implant, suitable methods for localization are two-dimensional X-ray and X-ray computerized tomography (CT scan). Ultrasound scanning (USS) with a high-frequency linear array transducer (10 MHz or greater) or magnetic resonance imaging (MRI) may be used. If these methods fail, call the Organon Service Center at 1-844-674-3200 for information on the procedure for measuring etonogestrel blood levels which can be used for verification of the presence of the implant. Until the presence of the implant has been verified, the woman should be advised to use a non-hormonal contraceptive method, such as condoms. Deeply-placed implants should be localized and removed as soon as possible to avoid the potential for distant migration [see Warnings and Precautions (5.1) ] . Figure 1 Figure Figure 2a Figure 2b Figure 2c Figure 3 Figure 4 Figure 5a Figure Figure 5b Figure 6 Figure 7 Figure 8a Figure 8b Figure 8c Figure 9 2.3 Removal of NEXPLANON Preparation Removal of the implant should only be performed under aseptic conditions by a healthcare professional who is familiar with the removal technique. If you are unfamiliar with the removal technique, call 1-844-674-3200 for further information. Before initiating the removal procedure, the healthcare professional should assess the location of the implant and carefully read the instructions for removal. The exact location of the implant in the arm should be verified by palpation. If the implant is not palpable, consult the medical record to verify the arm which contains the implant. If the implant cannot be palpated, it may be deeply located or have migrated. Consider that it may lie close to vessels and nerves. Removal of non-palpable implants should only be performed by a healthcare professional experienced in removing deeply placed implants and familiar with localizing the implant and the anatomy of the arm. Call 1-844-674-3200 for further information. [See Localization and Removal of a Non-Palpable Implant , below.] Figure Procedure for Removal of an Implant that is Palpable Before removal of the implant, the healthcare professional should confirm that: The woman does not have allergies to the antiseptic or anesthetic to be used. The following equipment is needed for removal of the implant: An examination table for the woman to lie on Sterile surgical drapes, sterile gloves, antiseptic solution, surgical marker Local anesthetic, needles, and syringe Sterile scalpel, forceps (straight and curved mosquito) Skin closure, sterile gauze, and pressure bandage Removal Procedure For illustrative purposes, Figures depict the left inner arm Step 1. Have the woman lie on her back on the table. The arm should be positioned with the elbow flexed and the hand underneath the head (or as close as possible). (See Figure 1 .) Step 2. Locate the implant by palpation. Push down the end of the implant closest to the shoulder ( Figure 10 ) to stabilize it; a bulge should appear indicating the tip of the implant that is closest to the elbow. If the tip does not pop up, removal of the implant may be more challenging and should be performed by professionals experienced with removing deeper implants. Call 1-844-674-3200 for further information. Mark the distal end (end closest to the elbow), for example, with a surgical marker. Figure 10 P – Proximal (toward the shoulder) D – Distal (toward the elbow) Step 3. Clean the site with an antiseptic solution. Step 4. Anesthetize the site, for example, with 0.5 to 1 mL 1% lidocaine, where the incision will be made ( Figure 11 ). Be sure to inject the local anesthetic under the implant to keep the implant close to the skin surface. Injection of local anesthetic over the implant may make removal more difficult. Figure 11 Step 5. Push down the end of the implant closest to the shoulder ( Figure 12 ) to stabilize it throughout the procedure. Starting over the tip of the implant closest to the elbow, make a longitudinal (parallel to the implant) incision of 2 mm towards the elbow. Take care not to cut the tip of the implant. Figure 12 Step 6. The tip of the implant should pop out of the incision. If it does not, gently push the implant towards the incision until the tip is visible. Grasp the implant with forceps and, if possible, remove the implant ( Figure 13 ). If needed, gently remove adherent tissue from the tip of the implant using blunt dissection. If the implant tip is not exposed following blunt dissection, make an incision into the tissue sheath and then remove the implant with the forceps ( Figures 14 and 15 ). Figure 13 Figure 14 Figure 15 Step 7. If the tip of the implant does not become visible in the incision, insert forceps (preferably curved mosquito forceps, with the tips pointed up) superficially into the incision ( Figure 16 ). Gently grasp the implant and then flip the forceps over into your other hand ( Figure 17 ). Figure 16 Figure 17 Step 8. With a second pair of forceps carefully dissect the tissue around the implant and grasp the implant ( Figure 18 ). The implant can then be removed . If the implant cannot be grasped, stop the procedure and refer the woman to a healthcare professional experienced with complex removals or call 1-844-674-3200. Figure 18 Step 9. Confirm that the entire implant, which is 4 cm long, has been removed by measuring its length. There have been reports of broken implants while in the patient's arm. In some cases, difficult removal of the broken implant has been reported. If a partial implant (less than 4 cm) is removed, the remaining piece should be removed by following the instructions in section 2.3. If the woman would like to continue using NEXPLANON, a new implant may be inserted immediately after the old implant is removed using the same incision as long as the site is in the correct location [see Dosage and Administration (2.4) ] . Step 10. After removing the implant, close the incision with a sterile adhesive wound closure. Step 11. Apply a pressure bandage with sterile gauze to minimize bruising. The woman may remove the pressure bandage in 24 hours and the sterile adhesive wound closure in 3 to 5 days. Figure Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure Figure 18 Localization and Removal of a Non-Palpable Implant There have been reports of migration of the implant; usually this involves minor movement relative to the original position [see Warnings and Precautions (5.1) ] , but may lead to the implant not being palpable at the location in which it was placed. An implant that has been deeply inserted or has migrated may not be palpable and therefore imaging procedures, as described below, may be required for localization. A non-palpable implant should always be located prior to attempting removal. Given the radiopaque nature of the implant, suitable methods for localization include two-dimensional X-ray and X-ray computer tomography (CT). Ultrasound scanning (USS) with a high-frequency linear array transducer (10 MHz or greater) or magnetic resonance imaging (MRI) may be used. Once the implant has been localized in the arm, the implant should be removed by a healthcare professional experienced in removing deeply placed implants and familiar with the anatomy of the arm . The use of ultrasound guidance during the removal should be considered. If the implant cannot be found in the arm after comprehensive localization attempts, consider applying imaging techniques to the chest as events of migration to the pulmonary vasculature have been reported. If the implant is located in the chest, surgical or endovascular procedures may be needed for removal; healthcare professionals familiar with the anatomy of the chest should be consulted. If at any time these imaging methods fail to locate the implant, etonogestrel blood level determination can be used for verification of the presence of the implant. For details on etonogestrel blood level determination, call 1-844-674-3200 for further instructions. If the implant migrates within the arm, removal may require a minor surgical procedure with a larger incision or a surgical procedure in an operating room. Removal of deeply-inserted implants should be conducted with caution to help prevent injury to deeper neural or vascular structures in the arm. Non-palpable and deeply-inserted implants should be removed by healthcare professionals familiar with the anatomy of the arm and removal of deeply-inserted implants. Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged. 2.4 Replacing NEXPLANON Immediate replacement can be done after removal of the previous implant and is similar to the insertion procedure described in section 2.2 Insertion of NEXPLANON. The new implant may be inserted in the same arm, and through the same incision from which the previous implant was removed, if the site is in the correct location, i.e., 8-10 cm from the medial epicondyle of the humerus and 3-5 cm posterior to (below) the sulcus [see Dosage and Administration (2.2) ] . If the same incision is being used to insert a new implant, anesthetize the insertion site [for example, 2 mL lidocaine (1%)] applying it just under the skin along the 'insertion canal.' Follow the subsequent steps in the insertion instructions [see Dosage and Administration (2.2) ] .

1 INDICATIONS AND USAGE NEXPLANON ® is indicated for use by women to prevent pregnancy. NEXPLANON is a progestin indicated for use by women to prevent pregnancy. ( 1 )

10 OVERDOSAGE Overdosage may result if more than one implant is inserted. In case of suspected overdose, the implant should be removed.

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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The contraceptive effect of NEXPLANON is achieved by suppression of ovulation, increased viscosity of the cervical mucus, and alterations in the endometrium. 12.2 Pharmacodynamics Exposure-response relationships of NEXPLANON are unknown. 12.3 Pharmacokinetics Absorption After subdermal insertion of the etonogestrel implant, etonogestrel is released into the circulation and is approximately 100% bioavailable. In a three-year clinical trial, NEXPLANON and the non-radiopaque etonogestrel implant (IMPLANON) yielded comparable systemic exposure to etonogestrel. For NEXPLANON, the mean (± SD) maximum serum etonogestrel concentrations were 1200 (± 604) pg/mL and were reached within the first two weeks after insertion (n=50). The mean (± SD) serum etonogestrel concentration decreased gradually over time, declining to 202 (± 55) pg/mL at 12 months (n=41), 164 (± 58) pg/mL at 24 months (n=37), and 138 (± 43) pg/mL at 36 months (n=32). For the non-radiopaque etonogestrel implant (IMPLANON), the mean (± SD) maximum serum etonogestrel concentrations were 1145 (± 577) pg/mL and were reached within the first two weeks after insertion (n=53). The mean (± SD) serum etonogestrel concentration decreased gradually over time, declining to 223 (± 73) pg/mL at 12 months (n=40), 172 (± 77) pg/mL at 24 months (n=32), and 153 (± 52) pg/mL at 36 months (n=30). The pharmacokinetic profile of NEXPLANON is shown in Figure 21 . Figure 21: Mean (± SD) Serum Concentration-Time Profile of Etonogestrel After Insertion of NEXPLANON During 3 Years of Use Figure 21 Distribution The apparent volume of distribution averages about 201 L. Etonogestrel is approximately 32% bound to sex hormone binding globulin (SHBG) and 66% bound to albumin in blood. Metabolism In vitro data shows that etonogestrel is metabolized in liver microsomes by the cytochrome P450 3A4 isoenzyme. The biological activity of etonogestrel metabolites is unknown. Excretion The elimination half-life of etonogestrel is approximately 25 hours. Excretion of etonogestrel and its metabolites, either as free steroid or as conjugates, is mainly in urine and to a lesser extent in feces. After removal of the implant, etonogestrel concentrations decreased below sensitivity of the assay by one week.

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

12.2 Pharmacodynamics Exposure-response relationships of NEXPLANON are unknown.

12.3 Pharmacokinetics Absorption After subdermal insertion of the etonogestrel implant, etonogestrel is released into the circulation and is approximately 100% bioavailable. In a three-year clinical trial, NEXPLANON and the non-radiopaque etonogestrel implant (IMPLANON) yielded comparable systemic exposure to etonogestrel. For NEXPLANON, the mean (± SD) maximum serum etonogestrel concentrations were 1200 (± 604) pg/mL and were reached within the first two weeks after insertion (n=50). The mean (± SD) serum etonogestrel concentration decreased gradually over time, declining to 202 (± 55) pg/mL at 12 months (n=41), 164 (± 58) pg/mL at 24 months (n=37), and 138 (± 43) pg/mL at 36 months (n=32). For the non-radiopaque etonogestrel implant (IMPLANON), the mean (± SD) maximum serum etonogestrel concentrations were 1145 (± 577) pg/mL and were reached within the first two weeks after insertion (n=53). The mean (± SD) serum etonogestrel concentration decreased gradually over time, declining to 223 (± 73) pg/mL at 12 months (n=40), 172 (± 77) pg/mL at 24 months (n=32), and 153 (± 52) pg/mL at 36 months (n=30). The pharmacokinetic profile of NEXPLANON is shown in Figure 21 . Figure 21: Mean (± SD) Serum Concentration-Time Profile of Etonogestrel After Insertion of NEXPLANON During 3 Years of Use Figure 21 Distribution The apparent volume of distribution averages about 201 L. Etonogestrel is approximately 32% bound to sex hormone binding globulin (SHBG) and 66% bound to albumin in blood. Metabolism In vitro data shows that etonogestrel is metabolized in liver microsomes by the cytochrome P450 3A4 isoenzyme. The biological activity of etonogestrel metabolites is unknown. Excretion The elimination half-life of etonogestrel is approximately 25 hours. Excretion of etonogestrel and its metabolites, either as free steroid or as conjugates, is mainly in urine and to a lesser extent in feces. After removal of the implant, etonogestrel concentrations decreased below sensitivity of the assay by one week.

20230929

5

3 DOSAGE FORMS AND STRENGTHS 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 etonogestrel ETONOGESTREL ETONOGESTREL BARIUM SULFATE MAGNESIUM STEARATE ETHYLENE-VINYL ACETATE COPOLYMER (28% VINYL ACETATE) white/off-white

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 24-month carcinogenicity study in rats with subdermal implants releasing 10 and 20 mcg etonogestrel per day (equal to approximately 1.8-3.6 times the systemic steady state exposure in women using NEXPLANON), no drug-related carcinogenic potential was observed. Etonogestrel was not genotoxic in the in vitro Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells or in the in vivo mouse micronucleus test. Fertility in rats returned after withdrawal from treatment.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 24-month carcinogenicity study in rats with subdermal implants releasing 10 and 20 mcg etonogestrel per day (equal to approximately 1.8-3.6 times the systemic steady state exposure in women using NEXPLANON), no drug-related carcinogenic potential was observed. Etonogestrel was not genotoxic in the in vitro Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells or in the in vivo mouse micronucleus test. Fertility in rats returned after withdrawal from treatment.

NDA021529

Nexplanon

etonogestrel

78206-145

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

PRINCIPAL DISPLAY PANEL - 68 mg Implant Blister Pack Carton NDC 78206-145-01 1 applicator containing 1 subdermal implant Nexplanon ® (etonogestrel implant) 68 mg Radiopaque Subdermal Use Only This product is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases. Rx only PRINCIPAL DISPLAY PANEL - 68 mg Implant Blister Pack Carton

Dosage and Administration, Insertion of NEXPLANON ( 2.2 ) 09/2023 Warnings and Precautions, Complications of Insertion/Removal and Broken/Bent Implants ( 5.1 ) 09/2023

Manufactured for: Organon USA LLC, a subsidiary of ORGANON & Co., Jersey City, NJ 07302, USA Manufactured by: N.V. Organon, Oss, The Netherlands, a subsidiary of Organon & Co., Jersey City, NJ 07302, USA For patent information: www.organon.com/our-solutions/patent/ © 2023 Organon group of companies. All rights reserved. uspi-og8415-iptx-2309r002

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Counsel women about the insertion and removal procedure of the NEXPLANON implant. Provide the woman with a copy of the Patient Labeling and ensure that she understands the information in the Patient Labeling before insertion and removal. Counsel women to contact their healthcare professional immediately if, at any time, they are unable to palpate the implant. Counsel women that NEXPLANON does not protect against HIV infection (AIDS) or other sexually transmitted diseases. Counsel women that the use of NEXPLANON may be associated with changes in their normal menstrual bleeding patterns so that they know what to expect. MRI Safety Information: NEXPLANON is MR safe.

14 CLINICAL STUDIES 14.1 Pregnancy In clinical trials of up to 3 years duration that involved 923 subjects, 18-40 years of age at entry, and 1756 women-years of use with the non-radiopaque etonogestrel implant (IMPLANON), the total exposures expressed as 28-day cycle equivalents by study year were: Year 1: 10,866 cycles Year 2: 8,581 cycles Year 3: 3,442 cycles The clinical trials excluded women who: Weighed more than 130% of their ideal body weight Were chronically taking medications that induce liver enzymes In the subgroup of women, 18-35 years of age at entry, 6 pregnancies during 20,648 cycles of use were reported. Two pregnancies occurred in each of Years 1, 2, and 3. Each conception was likely to have occurred shortly before or within 2 weeks after removal of the non-radiopaque etonogestrel implant. With these 6 pregnancies, the cumulative Pearl Index was 0.38 pregnancies per 100 women-years of use. 14.2 Return to Ovulation In clinical trials with the non-radiopaque etonogestrel implant (IMPLANON), the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired. 14.3 Implant Insertion and Removal Characteristics Out of 301 insertions of the NEXPLANON implant in a clinical trial, the mean insertion time (from the removal of the protection cap of the applicator until retraction of the needle from the arm) was 27.9 ± 29.3 seconds. After insertion, 300 out of 301 (99.7%) NEXPLANON implants were palpable. The single, non-palpable implant was not inserted according to the instructions. For 112 out of 114 (98.2%) subjects in 2 clinical trials for whom insertion and removal data were available, NEXPLANON implants were clearly visible with use of two-dimensional x-ray after insertion. The two implants that were not clearly visible after insertion were clearly visible with two-dimensional x-ray before removal.

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

8.4 Pediatric Use Safety and efficacy of NEXPLANON have been established in women of reproductive age. Safety and efficacy of NEXPLANON are expected to be the same for postpubertal adolescents. However, no clinical studies have been conducted in women less than 18 years of age. Use of this product before menarche is not indicated.

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 USE IN SPECIFIC POPULATIONS Pregnancy: Discontinue if maintaining a pregnancy. ( 8.1 ) Overweight women: NEXPLANON may become less effective in overweight women over time, especially in the presence of other factors that decrease etonogestrel concentrations, such as concomitant use of hepatic enzyme inducers. ( 8.7 ) 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 Safety and efficacy of NEXPLANON have been established in women of reproductive age. Safety and efficacy of NEXPLANON are expected to be the same for postpubertal adolescents. However, no clinical studies have been conducted in women less than 18 years of age. Use of this product before menarche is not indicated. 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) ] . 8.7 Overweight Women The effectiveness of the etonogestrel implant in women who weighed more than 130% of their ideal body weight has not been defined because such women were not studied in clinical trials. Serum concentrations of etonogestrel are inversely related to body weight and decrease with time after implant insertion. It is therefore possible that NEXPLANON may be less effective in overweight women, especially in the presence of other factors that decrease serum etonogestrel concentrations such as concomitant use of hepatic enzyme inducers.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied NEXPLANON is supplied as follows: NDC 78206-145-01 One NEXPLANON package consists of a single implant containing 68 mg etonogestrel, 15 mg of barium sulfate and 0.1 mg of magnesium stearate that is 4 cm in length and 2 mm in diameter, which is pre-loaded in the needle of a disposable applicator. The sterile applicator containing the implant is packed in a blister pack. 16.2 Storage and Handling Store NEXPLANON (etonogestrel implant) Radiopaque at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) [see USP Controlled Room Temperature]. Avoid storing NEXPLANON at temperatures above 30ºC (86ºF).

16.2 Storage and Handling Store NEXPLANON (etonogestrel implant) Radiopaque at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) [see USP Controlled Room Temperature]. Avoid storing NEXPLANON at temperatures above 30ºC (86ºF).