Nexplanon

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 18). Each implant consists of an ethylene vinyl acetate (EVA) copolymer core, containing 68 mg of the synthetic progestin etonogestrel, barium sulfate (radiopaque ingredient), and may also contain magnesium stearate, 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 18

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 19).

Figure 19

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

Contraindications

Documented hypersensitivity

Active or history of breast cancer

Arterial thromboembolic disease (stroke, MI), thrombophlebitis, DVT/PE, thrombogenic valvular disease

Estrogen-dependent neoplasia, liver disease, liver tumors

Undiagnosed abnormal vaginal bleeding

Uncontrolled hypertension

Diabetes mellitus with vascular involvement

Jaundice with prior oral contraceptive use

Hypersensitivity to etonogestrel or component of the formulation

Current/history of thrombophlebitis, thromboembolic disorders

Missed abortion

Cautions

Caution in family history of breast cancer and or DVT/PE, current/history of depression, endometriosis, DM, HTN, bone mineral density changes, renal/hepatic impairment, bone metabolic disease, SLE; conditions exacerbated by fluid retention (eg, migraine, asthma, epilepsy).

Discontinue if the following develop jaundice, visual problems (may cause contact lens intolerance), any signs of VTE, migraine with unusual severity, severe depression, increased risk of thromboembolic complications after surgery.

May cause retinal vascular thrombosis; discontinue if loss of vision, migraine proptosis, diplopia or other visual disturbances occur

Discontinue 4 week before major surgery or prolonged immobilization

Use caution in patients on warfarin, oral anticoagulants (increase in anticoagulant dose may be warranted)

Some studies link OCP use with increased risk of breast cancer, whereas other studies have not shown a change in risk; woman's risk depends on conditions where naturally high hormone levels persist for long periods of time including early onset menstruation before age 12, late onset menopause, after age 55, first child after age 30, nulliparity

Increased risk of cervical cancer with OCP use, however HPV remains as main risk factor for this cancer; evidence suggests long-term use of OCPs, 5 or more years, may be associated with increased risk

Increased risk of liver cancer with OCP use; risk increases with longer duration of OCP use

Be alert to the possibility of an ectopic pregnancy in women receiving therapy who become pregnant or complain of lower abdominal pain

Counsel women regarding changes in bleeding frequency, intensity, or duration

Implant should be removed in the event of a thrombosis

Implant should be removed if blood pressure rises significantly and becomes uncontrolled

When implant broken or bent, may increase release rate of etonogestrel; when implant removed, remove it in its entirety

Monitor prediabetic and diabetic women receiving therapy

Complications of Insertion

• Implant removal may be difficult or impossible if implant not inserted correctly, inserted too deeply, not palpable, encased in fibrous tissue, or has migrated
• Exploratory surgery without knowledge of exact location of implant is strongly discouraged
• Migration of implant within arm from insertion site, which may be related to deep insertion, reported; in cases where implant has migrated to pulmonary artery, endovascular or surgical procedures may be needed for removal
• If at any time implant cannot be palpated, it should be localized; removal is recommended

• Organon Pharmaceuticals USA

Before taking Nexplanon, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed
• are allergic to Nexplanon or to any of its ingredients 
• have or have a history of blood clots
• have active liver disease or liver tumors
• have undiagnosed abnormal vaginal bleeding
• have or suspect you may have breast cancer
• have a history of ectopic pregnancy
• have a history of ovarian cysts
• have a history of high blood pressure
• have a history of gallbladder disease
• have diabetes or prediabetes
• have a history of depression
• have heart failure
• have high cholesterol

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

In the U.S.

• Implanon
• Nexplanon

Available Dosage Forms:

• Implant

Therapeutic Class: Contraceptive, Progestin

Pharmacologic Class: Progestin

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

The efficacy of Nexplanon does not depend on daily, weekly or monthly administration.

All healthcare providers should receive instruction and training prior to performing insertion and/or removal of Nexplanon.

A single Nexplanon implant is inserted subdermally in the upper arm. To reduce the risk of neural or vascular injury, the implant should be inserted at the inner side of the non-dominant upper arm about 8-10 cm (3-4 inches) above the medial epicondyle of the humerus. The implant should be inserted subdermally just under the skin, avoiding the sulcus (groove) between the biceps and triceps muscles and the large blood vessels and nerves that lie there in the neurovascular bundle deeper in the subcutaneous tissues. An implant inserted more deeply than subdermally (deep insertion) may not be palpable and the localization and/or removal can be 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.

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.

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 provider and the woman should be able to feel the implant under the skin after placement.

All healthcare providers performing insertions and/or removals of Nexplanon should receive instructions and training prior to inserting or removing the implant. Information concerning the insertion and removal of Nexplanon will be sent upon request free of charge [1-877-467-5266].

Preparation

Prior to inserting Nexplanon carefully read the instructions for insertion as well as the full prescribing information.

Before insertion of Nexplanon, the healthcare provider should confirm that:

• The woman is not pregnant nor has any 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 has reviewed and completed a consent form to be maintained with the woman's chart.
• 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, sterile marker (optional)
• Local anesthetic, needles, and syringe
• Sterile gauze, adhesive bandage, pressure bandage

Insertion Procedure

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 wrist is parallel to her ear or her hand is positioned next to her head (Figure 1).

Figure 1

Step 2. Identify the insertion site, which is at the inner side of the non-dominant upper arm about 8-10 cm (3-4 inches) above the medial epicondyle of the humerus, avoiding the sulcus (groove) between the biceps and triceps muscles and the large blood vessels and nerves that lie there in the neurovascular bundle deeper in the subcutaneous tissue (Figure 2). The implant should be inserted subdermally just under the skin [see Warnings and Precautions (5.1)].

Step 3. Make two marks with a sterile marker: first, mark the spot where the etonogestrel implant will be inserted, and second, mark a spot a few centimeters proximal to the first mark (Figure 2). This second mark will later serve as a direction guide during insertion.

Figure 2

Step 4. Clean the insertion site with an antiseptic solution.

Step 5. 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 6. Remove the sterile preloaded disposable Nexplanon applicator carrying the implant from its blister. The applicator should not be used if sterility is in question.

Step 7. 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 can 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 it will retract the needle and prematurely release the implant from the applicator.

Figure 3

Step 8. With your free hand, stretch the skin around the insertion site with thumb and index finger (Figure 4).

Figure 4

Step 9. Puncture the skin with the tip of the needle slightly angled less than 30° (Figure 5).

Figure 5

Step 10. Lower the applicator to a horizontal position. While lifting the skin with the tip of the needle (Figure 6), slide the needle to its full length. 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.

You can best see movement of the needle, and that it is inserted just under the skin, if you are seated and are looking at the applicator from the side and NOT from above. In this position, you can clearly see the insertion site and the movement of the needle just under the skin.

Figure 6

Step 11. Keep the applicator in the same position with the needle inserted to its full length. If needed, you may use your free hand to keep the applicator in the same position during the following procedure. Unlock the purple slider by pushing it slightly down. Move the slider fully back until it stops (Figure 7). 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. If the applicator is not kept in the same position during this procedure or if the purple slider is not completely moved to the back, the implant will not be inserted properly.

Figure 7

Step 12. 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 8). See "If the rod is not palpable" below.

Figure 8

Step 13. Place a small adhesive bandage over the insertion site. Request that the woman palpate the implant.

Step 14. Apply a pressure bandage with sterile gauze to minimize bruising. The woman may remove the pressure bandage in 24 hours and the small bandage over the insertion site after 3 to 5 days.

Step 15. Complete the USER CARD and give it to the woman to keep. Also, complete the PATIENT CHART LABEL and affix it to the woman's medical record.

Step 16. 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:

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 1-877-467-5266 for information on the procedure for measuring etonogestrel blood levels.

Until the presence of the implant has been verified, the woman should be advised to use a non-hormonal contraceptive method, such as condoms.

Once the non-palpable implant has been located, removal is recommended [see Warnings and Precautions (5.1)].

Removal of Nexplanon

Preparation

Before initiating the removal procedure, the healthcare provider should carefully read the instructions for removal and consult the USER CARD and/or the PATIENT CHART LABEL for the location of the implant. The exact location of the implant in the arm should be verified by palpation. [See Dosage and Administration (2.3) and Localization and Removal of a Non-Palpable Implant.]

Procedure for Removal of an Implant that is Palpable

Before removal of the implant, the healthcare provider should confirm that:

• The woman does not have allergies to the antiseptic or anesthetic to be used.

Remove the implant under aseptic conditions.

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, sterile marker (optional)
• Local anesthetic, needles, and syringe
• Sterile scalpel, forceps (straight and curved mosquito)
• Skin closure, sterile gauze, adhesive bandage and pressure bandages

Removal Procedure

Step 1. Clean the site where the incision will be made and apply an antiseptic. Locate the implant by palpation and mark the distal end (end closest to the elbow), for example, with a sterile marker (Figure 9).

Figure 9

Step 2. Anesthetize the arm, for example, with 0.5 to 1 mL 1% lidocaine at the marked site where the incision will be made (Figure 10). Be sure to inject the local anesthetic under the implant to keep it close to the skin surface.

Figure 10

Step 3. Push down the proximal end of the implant (Figure 11) to stabilize it; a bulge may appear indicating the distal end of the implant. Starting at the distal tip of the implant, make a longitudinal incision of 2 mm towards the elbow.

Figure 11

Step 4. Gently push the implant towards the incision until the tip is visible. Grasp the implant with forceps (preferably curved mosquito forceps) and gently remove the implant (Figure 12).

Figure 12

Step 5. If the implant is encapsulated, make an incision into the tissue sheath and then remove the implant with the forceps (Figures 13 and 14).

Step 6. If the tip of the implant does not become visible in the incision, gently insert a forceps into the incision (Figure 15). Flip the forceps over into your other hand (Figure 16).

Step 7. With a second pair of forceps carefully dissect the tissue around the implant and grasp the implant (Figure 17). The implant can then be removed.

Figure 17

Step 8. 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. [See Dosage and Administration (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 [see Dosage and Administration (2.4)].

Step 9. After removing the implant, close the incision with a steri-strip and apply an adhesive bandage.

Step 10. Apply a pressure bandage with sterile gauze to minimize bruising. The woman may remove the pressure bandage in 24 hours and the small bandage 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 according to the instructions in Dosage and Administration (2.3), Procedure for Removal of an Implant that is Palpable, and 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 providers 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 1-877-467-5266 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 in order to prevent injury to deeper neural or vascular structures in the arm and be performed by healthcare providers familiar with the anatomy of the arm.

Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged.

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 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)].

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)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, 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.

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.

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.

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 and/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.

Postmarketing Experience

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

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.

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

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

Nexplanon (etonogestrel) is a hormone implant that prevents ovulation (the release of an egg from an ovary). This medication also causes changes in your cervical mucus and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus.

Nexplanon is radiopaque implant used as contraception to prevent pregnancy. Etonogestrel is contained in a small plastic rod that is implanted into the skin of your upper arm. The medicine is released slowly into the body.

The Nexplanon rod can remain in place and provide continuous contraception for up to 3 years.

Nexplanon implants contain a small amount of barium sulfate so that the implant can be seen by X-ray.

You should not smoke while using a Nexplanon implant.

Nexplanon will not protect you from sexually transmitted diseases--including HIV and AIDS. Using a condom is the only way to protect yourself from these diseases.