Nexplanon: Package Insert / Prescribing Info

• 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

• 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.

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)].

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.]

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.

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.

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.

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

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.

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

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.