Implanon

Description

IMPLANON (etonogestrel implant) is a progestin-only, soft, flexible implant preloaded in a sterile, disposable applicator for subdermal use. The implant is off-white, non-biodegradable and 4 cm in length with a diameter of 2 mm (see Figure 22). Each implant consists of an ethylene vinylacetate (EVA) copolymer core, containing 68 mg of the synthetic progestin etonogestrel, surrounded by an EVA copolymer skin. Once inserted subdermally, the release rate is 60 to 70 mcg/day in Week 5 to 6 and decreases to approximately 35 to 45 mcg/day at the end of the first year, to approximately 30 to 40 mcg/day at the end of the second year, and then to approximately 25 to 30 mcg/day at the end of the third year. IMPLANON is a progestin-only contraceptive and does not contain estrogen. IMPLANON does not contain latex and is not radio-opaque.

Figure 22 (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 23).

Figure 23

 

NEXPLANON® is indicated for use by women to prevent pregnancy.

Dosage And Administration

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 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 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). 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 and WARNINGS AND PRECAUTIONS]. Â

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 Â

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 shouldreceive 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/orremove NEXPLANON, do not attempt the procedure.

Call the Merck National Service Center at 1-877-888-4231 if you have any questions. Videos demonstrating insertion and removal are available online for trained healthcare providers (www.nexplanontraining.com).

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].
• 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, 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 providersshould be positioned to see the advancement of the needle by viewing the applicator from theside 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 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]

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

 

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 carrying the implant from its blister. The applicator should not be used if sterility is in question.

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 youhave fully inserted the needle subdermally, as doing so will retract the needle and prematurely release the implant from the applicator.

Figure 3

 

Step 9. With your free hand, stretch the skin around the insertion site towards the elbow (Figure 4).

Figure 4

 

Step 10. The implant should be inserted subdermally just under the skin (see WARNINGS AND PRECAUTIONS)

To help make sure the implant is inserted just under the skin, you should positionyourself to see the advancement of the needle by viewing the applicator from the side and notfrom 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 11. Puncture the skin with the tip of the needle slightly angled less than 30° (Figure 5a).

Figure 5a

 

Step 12. Insert the needle until the bevel (slanted opening of the tip) is just under the skin (and no further) (Figure 5b). If you insert the needle past the bevel, withdraw it until only the bevel is beneath the skin.

Figure 5b

 

 

Step 13. 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 needleshould be pulled back and be readjusted to subdermal position before completing the insertion procedure.

Figure 6

 

Step 14. 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 purpleslider 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 15. Apply a small adhesive bandage over the insertion site.

Step 16. 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 17. Request that the woman palpate the implant.

Step 18. 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 19. 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 20. 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 beeninserted 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 Merck National Service Center at 1-877-888-4231 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 usea 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].

Removal Of NEXPLANON

Preparation

Removal of the implant should only be performed under aseptic conditions by a healthcare provider who is familiar with the removal technique. If you are unfamiliar with the removal technique, call 1-877-888-4231 for further information.

Before initiating the removal procedure, the healthcare provider 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 User Card or 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 provider experienced in removing deeply placed implants and familiar with localizing the implant and the anatomy of the arm. Call 1877-888-4231 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 provider 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 providers experienced with removing deeper implants. Call 1-877-888-4231 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 a 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 provider experienced with complexremovals or call 1-877-888-4231.

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].

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], 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 provider 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 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 1-877-888-4231 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 help prevent injury to deeper neural or vascular structures in the arm. Non-palpable and deeply inserted implants should be removed by healthcare providers 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 stronglydiscouraged.

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, as long as the site is in the correct location [see DOSAGE AND ADMINISTRATION]. 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].

How Supplied

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 is supplied as follows:

NDC 0052-4330-01

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.

Storage And Handling

Store NEXPLANON (etonogestrel implant) Radiopaque at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Avoid storing NEXPLANON at temperatures above 30°C (86°F).

Manufactured by: N.V. Organon, Oss, The Netherlands, a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. Revised: Oct 2018

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]
• Ectopic Pregnancies [see WARNINGS AND PRECAUTIONS]
• Thrombotic and Other Vascular Events [see WARNINGS AND PRECAUTIONS]
• Liver Disease [see WARNINGS AND PRECAUTIONS]

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.

Table 3: Adverse Reactions Leading to Discontinuation of Treatment in 1% or Moreof Subjects in Clinical Trials of the Non-Radiopaque Etonogestrel Implant (IMPLANON)

Adverse Reactions	All Studies N = 942
Bleeding Irregularities*	11.1%
Emotional Lability1″	2.3%
Weight Increase	2.3%
Headache	1.6%
Acne	1.3%
Depression*	1.0%
* Includes “frequent”, “heavy”, “prolonged”, “spotting”, and other patterns of bleeding irregularity. †Among US subjects (N=330), 6.1% experienced emotional lability that led to discontinuation. ‡Among US subjects (N=330), 2.4% experienced depression that led to discontinuation.

 

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 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 paresthesialike 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]. Surgical intervention might be necessary when removing the implant.

Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

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., etravirene]). 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.

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.

Included as part of the PRECAUTIONS section.

Precautions

The following information is based on experience with either IMPLANON, other progestin-only contraceptives, or experience with combination (estrogen plus progestin) oral contraceptives .

Complications Of Insertion And Removal

IMPLANON should be inserted subdermally so that it will be palpable after insertion, and this should be confirmed by palpation immediately after insertion. Failure to insert IMPLANON properly may go unnoticed unless it is palpated immediately after insertion. Undetected failure to insert the implant may lead to an unintended pregnancy. Complications related to insertion and removal procedures, such as pain, paresthesias, bleeding, hematoma, scarring or infection, may occur. Occasionally in postmarketing use, implant insertions have failed because the implant fell out of the needle or remained in the needle during insertion.

If IMPLANON is inserted deeply (intramuscular or in the fascia), neural or vascular injury may occur. To reduce the risk of neural or vascular injury, IMPLANON 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. IMPLANON 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. Deep insertions of IMPLANON have been associated with paraesthesia (due to neural injury), migration of the implant (due to intramuscular or fascial insertion), and intravascular insertion. If infection develops at the insertion site, start suitable treatment. If the infection persists, the implant should be removed. Incomplete insertions or infections may lead to expulsion.

Implant removal may be difficult or impossible if the implant is not inserted correctly, is inserted too deeply, not palpable, encased in fibrous tissue, or has migrated.

There have been reports of migration of the implant within the arm from the insertion site, which may be related to a deep insertion. There also have been postmarketing reports of implants located within the vessels of the arm and the pulmonary artery, which may be related to deep insertions or intravascular insertion. In cases where the implant has migrated to the pulmonary artery, endovascular procedures may be needed for removal.

If at any time the implant cannot be palpated, it should be localized and removal is recommended.

Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged. Removal of deeply inserted implants should be conducted with caution in order to prevent injury to deeper neural or vascular structures in the arm and be performed by healthcare providers familiar with the anatomy of the arm. If the implant is located in the chest, healthcare providers familiar with the anatomy of the chest should be consulted. Failure to remove the implant may result in continued effects of etonogestrel, such as compromised fertility, ectopic pregnancy, or persistence or occurrence of a drug-related adverse event.

Changes In Menstrual Bleeding Patterns

After starting IMPLANON, women are likely to have a change from their normal menstrual bleeding pattern. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration. In clinical trials, bleeding patterns ranged from amenorrhea (1 in 5 women) to frequent and/or prolonged bleeding (1 in 5 women). The bleeding pattern experienced during the first three months of IMPLANON use is broadly predictive of the future bleeding pattern for many women. Women should be counseled regarding the bleeding pattern changes they may experience so that they know what to expect. Abnormal bleeding should be evaluated as needed to exclude pathologic conditions or pregnancy.

In clinical studies of IMPLANON, reports of changes in bleeding pattern were the most common reason for stopping treatment (11.1%). Irregular bleeding (10.8%) was the single most common reason women stopped treatment, while amenorrhea (0.3%) was cited less frequently. In these studies, women had an average of 17.7 days of bleeding or spotting every 90 days (based on 3,315 intervals of 90 days recorded by 780 patients). The percentages of patients having 0, 1-7, 8-21, or > 21 days of spotting or bleeding over a 90-day interval while using the IMPLANON implant are shown in Table 1.

Table 1: Percentages of Patients with 0, 1 – 7, 8 – 21, or > 21 Days of Spotting or Bleeding Over a 90-Day Interval While Using IMPLANON

Total Days of Spotting or Bleeding	Percentage of Patients
	Treatment Days 91-180 (N = 745)	Treatment Days 271-360 (N = 657)	Treatment Days 631-720 (N = 547)
0 Days	19%	24%	17%
1-7 Days	15%	13%	12%
8-21 Days	30%	30%	37%
> 21 Days	35%	33%	35%

 

Bleeding patterns observed with use of IMPLANON for up to 2 years, and the proportion of 90-day intervals with these bleeding patterns, are summarized in Table 2.

Table 2: Bleeding Patterns Using IMPLANON during the First 2 Years of Use*

BLEEDING PATTERNS	DEFINITIONS	% †
Infrequent	Less than three bleeding and/or spotting episodes in 90 days (excluding amenorrhea)	33.6
Amenorrhea	No bleeding and/or spotting in 90 days	22.2
Prolonged	Any bleeding and/or spotting episode lasting more than 14 days in 90 days	17.7
Frequent	More than 5 bleeding and/or spotting episodes in 90 days	6.7
*Based on 3,315 recording periods of 90 day’s duration in 780 women, excluding the first 90 days after implant insertion †% = Percentage of 90-day intervals with this pattern

 

In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy.

Ectopic Pregnancies

As with all progestin-only contraceptive products, be alert to the possibility of an ectopic pregnancy among women using IMPLANON who become pregnant or complain of lower abdominal pain. Although ectopic pregnancies are uncommon among women using IMPLANON, a pregnancy that occurs in a woman using IMPLANON may be more likely to be ectopic than a pregnancy occurring in a woman using no contraception.

Thrombotic And Other Vascular Events

The use of combination hormonal contraceptives (progestin plus estrogen) increases the risk of vascular events, including arterial events (strokes and myocardial infarctions) or deep venous thrombotic events (venous thromboembolism, deep venous thrombosis, retinal vein thrombosis, and pulmonary embolism). IMPLANON is a progestin-only contraceptive. It is unknown whether this increased risk is applicable to etonogestrel alone. It is recommended, however, that women with risk factors known to increase the risk of venous and arterial thromboembolism be carefully assessed.

There have been postmarketing reports of serious arterial thrombotic and venous thromboembolic events, including cases of pulmonary emboli (some fatal), deep vein thrombosis, myocardial infarction, and strokes, in women using IMPLANON. IMPLANON should be removed in the event of a thrombosis.

Due to the risk of thromboembolism associated with pregnancy and immediately following delivery, IMPLANON should not be used prior to 21 days postpartum. Women with a history of thromboembolic disorders should be made aware of the possibility of a recurrence.

Evaluate for retinal vein thrombosis immediately if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.

Consider removal of the IMPLANON implant in case of long-term immobilization due to surgery or illness.

Ovarian Cysts

If follicular development occurs, atresia of the follicle is sometimes delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally, these enlarged follicles disappear spontaneously. On rare occasion, surgery may be required.

Carcinoma Of The Breast And Reproductive Organs

Women who currently have or have had breast cancer should not use hormonal contraception because breast cancer may be hormonally sensitive [see CONTRAINDICATIONS]. Some studies suggest that the use of combination hormonal contraceptives might increase the incidence of breast cancer; however, other studies have not confirmed such findings.

Some studies suggest that the use of combination hormonal contraceptives is associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which such findings are due to differences in sexual behavior and other factors.

Women with a family history of breast cancer or who develop breast nodules should be carefully monitored.

Liver Disease

Disturbances of liver function may necessitate the discontinuation of hormonal contraceptive use until markers of liver function return to normal. Remove IMPLANON if jaundice develops.

Hepatic adenomas are associated with combination hormonal contraceptives use. An estimate of the attributable risk is 3.3 cases per 100,000 for combination hormonal contraceptives users. It is not known whether a similar risk exists with progestin-only methods like IMPLANON.

The progestin in IMPLANON may be poorly metabolized in women with liver impairment. Use of IMPLANON in women with active liver disease or liver cancer is contraindicated [see CONTRAINDICATIONS].

Weight Gain

In clinical studies, mean weight gain in US IMPLANON users was 2.8 pounds after 1 year and 3.7 pounds after 2 years. How much of the weight gain was related to the implant is unknown. In studies, 2.3% of the users reported weight gain as the reason for having the implant removed.

Elevated Blood Pressure

Women with a history of hypertension-related diseases or renal disease should be discouraged from using hormonal contraception. For women with well-controlled hypertension, use of IMPLANON can be considered. Women with hypertension using IMPLANON should be closely monitored. If sustained hypertension develops during the use of IMPLANON, or if a significant increase in blood pressure does not respond adequately to antihypertensive therapy, IMPLANON should be removed.

Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among combination hormonal contraceptive users. It is not known whether a similar risk exists with progestin-only methods like IMPLANON.

Carbohydrate And Lipid Metabolic Effects

Use of IMPLANON may induce mild insulin resistance and small changes in glucose concentrations of unknown clinical significance. Carefully monitor prediabetic and diabetic women using IMPLANON.

Women who are being treated for hyperlipidemia should be followed closely if they elect to use IMPLANON. Some progestins may elevate LDL levels and may render the control of hyperlipidemia more difficult.

Depressed Mood

Women with a history of depressed mood should be carefully observed. Consideration should be given to removing IMPLANON in patients who become significantly depressed.

Return To Ovulation

In clinical trials with 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.

Fluid Retention

Hormonal contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. It is unknown if IMPLANON causes fluid retention.

Contact Lenses

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

In Situ Broken Or Bent Implant

There have been reports of broken or bent implants while in the patient’s arm. Based on in vitro data, when the implant is broken or bent, the release rate of etonogestrel may be slightly increased.

When an implant is removed, it is important to remove it in its entirety [see DOSAGE AND ADMINISTRATION].

Monitoring

A woman who is using IMPLANON should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care.

Drug-Laboratory Test Interactions

Sex hormone-binding globulin concentrations may be decreased for the first 6 months after IMPLANON insertion followed by a gradual recovery. Thyroxine concentrations may initially be slightly decreased followed by gradual recovery to baseline.

Patient Counseling Information

“See FDA-Approved Patient Labeling (PATIENT INFORMATION)”

• Counsel women about the insertion and removal procedure of the IMPLANON 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. A USER CARD and consent form are included in the packaging. Have the woman complete a consent form and retain it in your records. The USER CARD should be filled out and given to the patient after insertion of the IMPLANON implant so that she will have a record of the location of the implant in the upper arm and when it should be removed.
• Counsel women to contact their healthcare provider immediately if, at any time, they are unable to palpate the implant.
• Counsel women that IMPLANON does not protect against HIV infection (AIDS) or other sexually transmitted diseases.
• Counsel women that the use of IMPLANON may be associated with changes in their normal menstrual bleeding patterns so that they know what to expect.

FDA-Approved Patient Labeling

See the full patient product information for IMPLANON.

Nonclinical Toxicology

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 IMPLANON), 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 returned after withdrawal from treatment.

Use In Specific Populations

Pregnancy

IMPLANON is not indicated for use during pregnancy [see CONTRAINDICATIONS].

Teratology studies have been performed in rats and rabbits using oral administration up to 390 and 790 times the human IMPLANON dose (based upon body surface) and revealed no evidence of fetal harm due to etonogestrel exposure.

Studies have revealed no increased risk of birth defects in women who have used combination oral contraceptives before pregnancy or during early pregnancy. There is no evidence that the risk associated with IMPLANON is different from that of combination oral contraceptives.

IMPLANON should be removed if maintaining a pregnancy.

Nursing Mothers

Based on limited clinical data, IMPLANON may be used during breastfeeding after the fourth postpartum week. Use of IMPLANON before the fourth postpartum week has not been studied. Small amounts of etonogestrel are excreted in breast milk. 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. The health of breast-fed infants whose mothers began using IMPLANON during the fourth to eighth week postpartum (n=38) was evaluated in a comparative study with infants of mothers using a non-hormonal IUD (n=33). They were breast-fed for a mean duration of 14 months and followed up to 36 months of age. No significant effects and no differences between the groups were observed on the physical and psychomotor development of these infants. No differences between groups in the production or quality of breast milk were detected.

Healthcare providers should discuss both hormonal and non-hormonal contraceptive options, as steroids may not be the initial choice for these patients.

Pediatric Use

Safety and efficacy of IMPLANON have been established in women of reproductive age. Safety and efficacy of IMPLANON 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.

Geriatric Use

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

Hepatic Impairment

No studies were conducted to evaluate the effect of hepatic disease on the disposition of IMPLANON. The use of IMPLANON in women with active liver disease is contraindicated [see CONTRAINDICATIONS].

Renal Impairment

No studies were conducted to evaluate the effect of renal disease on the disposition of IMPLANON.

Overweight Women

The effectiveness of IMPLANON 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 IMPLANON 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.

Overdosage may result if more than 1 implant is inserted. In case of suspected overdose, the implant should be removed.

Contraindications

IMPLANON 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 IMPLANON [see ADVERSE REACTIONS]

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.

Pharmacodynamics

Exposure-response relationships of NEXPLANON are unknown.

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

 

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.

Clinical Studies

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.

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.

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.