PRODUCT MONOGRAPH
INCLUDING PATIENT MEDICATION INFORMATION
NEXPLANON®
Etonogestrel extended release subdermal implant
Extended release implant, 68 mg per implant (to deliver up to 70 mcg etonogestrel per day), Subdermal Hormonal Contraceptive OrganonCanada Inc. 16766 route Transcanadienne Kirkland QC Canada H9H 4M7 www.organon.ca
Date of Initial Authorization: May 25, 2020
Date of Revision: April 13, 2021
RECENT MAJOR LABEL CHANGES
Warnings and Precautions (7), Broken or Bent Implant 04/2021
TABLE OF CONTENTS
Sections or subsections that are not applicable at the time of authorization are not listed.
RECENT MAJOR LABEL CHANGES ... 2
TABLE OF CONTENTS ... 2
PART I: HEALTH PROFESSIONAL INFORMATION ... 4
1
INDICATIONS ... 4
1.1
Pediatrics ... 4
1.2
Geriatrics ... 4
2
CONTRAINDICATIONS ... 4
3
SERIOUS WARNINGS AND PRECAUTIONS BOX ... 5
4
DOSAGE AND ADMINISTRATION ... 5
4.1
Dosing Considerations ... 5
4.2
Recommended Dose and Dosage Adjustment ... 5
4.4
Administration ... 6
5
OVERDOSAGE ... 19
6
DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ... 19
7
WARNINGS AND PRECAUTIONS ... 20
7.1
Special Populations ... 26
7.1.1
Pregnant Women ... 26
7.1.2
Breast-feeding ... 26
7.1.3
Pediatrics ... 26
7.1.4
Geriatrics ... 26
8
ADVERSE REACTIONS... 27
8.1
Adverse Reaction Overview ... 27
8.2
Clinical Trial Adverse Reactions ... 27
8.3
Less Common Clinical Trial Adverse Reactions ... 31
8.4
Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other
Quantitative Data ... 31
8.5
Post-Market Adverse Reactions ... 31
9
DRUG INTERACTIONS ... 32
9.2
Drug Interactions Overview ... 32
9.4
Drug-Drug Interactions ... 32
9.5
Drug-Food Interactions ... 33
9.6
Drug-Herb Interactions ... 33
9.7
Drug-Laboratory Test Interactions... 33
10
CLINICAL PHARMACOLOGY ... 33
10.1
Mechanism of Action ... 33
10.2
Pharmacodynamics ... 34
10.3
Pharmacokinetics ... 34
11
STORAGE, STABILITY AND DISPOSAL ... 36
12
SPECIAL HANDLING INSTRUCTIONS ... 36
PART II: SCIENTIFIC INFORMATION ... 37
13
PHARMACEUTICAL INFORMATION ... 37
14
CLINICAL TRIALS ... 37
14.1
Trial Design and Study Demographics ... 37
14.2
Study Results ... 39
14.3
Comparative Bioavailability Studies ... 40
15
NON-CLINICAL TOXICOLOGY ... 41
PART I: HEALTH PROFESSIONAL INFORMATION
1
INDICATIONS
NEXPLANON® is indicated for:
Prevention of pregnancy for up to 3 years 1.1 Pediatrics
Pediatrics (<18 years of age): Safety and efficacy have been studied in women between 18 and
40 years. NEXPLANON® is not indicated for use before menarche. No clinical studies have been
conducted in women less than 18 years of age; therefore, Health Canada has not authorized
an indication for pediatric use.
1.2 Geriatrics
Geriatrics (>65 years of age): This product has not been studied in women over 65 years of age
and is not indicated in postmenopausal women. No data are available to Health Canada;
therefore, Health Canada has not authorized an indication for geriatric use.
Overweight women
NEXPLANON® may become less effective in overweight women over time, especially in the
presence of other factors that decrease etonogestrel concentrations, such as concomitant use
of hepatic enzyme inducers. (see WARNINGS AND PRECAUTIONS / Overweight Women)
2
CONTRAINDICATIONS
NEXPLANON® is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a
complete listing, see Dosage Forms, Strengths, Composition and Packaging.
Progestin-only contraceptives should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during the use of NEXPLANON®, the product should be stopped immediately.
NEXPLANON® should not be used in women with: • Known or suspected pregnancy;
• Current or past history of thrombosis or thromboembolic disorders; • Liver tumours, 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;
3
SERIOUS WARNINGS AND PRECAUTIONS BOX
Serious Warnings and Precautions
NEXPLANON® should be inserted and/or removed by a Healthcare Professional familiar with use of the implant. All Healthcare Professionals should receive instruction and training prior to performing insertion and/or removal of NEXPLANON®, and, where appropriate, request supervision prior to inserting or removing the implant.
If at any time the implant is not palpable by the Healthcare Professional or the patient, NEXPLANON® should be localized as soon as possible and removed as soon as medically appropriate to manage the risks of migration. There have been post-marketing reports of
implants located within the vessels of the arm and the pulmonary artery which may be related to deep insertions or intravascular insertion.
Women should be counselled that NEXPLANON® DOES NOT PROTECT against sexually
transmitted infections (STIs) including HIV/AIDS. For protection against STIs, it is advisable to use latex or polyurethane condoms IN COMBINATION WITH NEXPLANON®.
4
DOSAGE AND ADMINISTRATION
4.1 Dosing ConsiderationsPregnancy should be excluded before insertion of NEXPLANON®.
NEXPLANON® should be inserted and/or removed by an HCP familiar with use of the implant. All HCPs should receive instruction and training prior to performing insertion and/or removal of NEXPLANON®, and, where appropriate, request supervision prior to inserting or removing the implant.
Before inserting the implant, carefully read and follow the instructions for insertion and removal of the implant (see 4.4 Administration / “How to insert NEXPLANON®” and “How to remove
NEXPLANON®”).
Videos demonstrating insertion and removal of the implant are available online. Please refer to
www.nexplanonvideos.com. HCPs may obtain more information about available training by visiting
www.etonogestrel-implant-training.ca. Please contact Organon Canada at 1-844-820-5468 if you have any questions.
The implant should not be inserted after the expiry date as indicated on the primary package.
If you are unsure of the necessary steps to safely insert and/or remove NEXPLANON®, do not attempt the procedure.
4.2 Recommended Dose and Dosage Adjustment
NEXPLANON® is a long-acting reversible hormonal contraceptive (LARC). A single implant is inserted subdermally and can be left in place for three years. Remove the implant no later than three years after the date of insertion. The user should be informed that she can request the removal of the implant at
any time. Healthcare professionals (HCPs) may consider earlier replacement of the implant in heavier women (see WARNINGS AND PRECAUTIONS / Endocrine and Metabolism / Body Weight). After the removal of the implant, immediate insertion of another implant will result in continued contraceptive protection. If the woman does not wish to continue using NEXPLANON®, but wants to continue preventing pregnancy, another contraceptive method should be recommended.
4.4 Administration
The basis for successful use and subsequent removal of the NEXPLANON® implant is a correct and
carefully performed subdermal insertion of the implant in accordance with the instructions. If the implant is not inserted in accordance with the instructions specified below in “How to insert NEXPLANON®”, and on the correct day in “When to insert Nexplanon®”, unintended pregnancy may occur. An implant inserted more deeply than subdermally (deep insertion) may not be palpable and the localization and/or removal can be difficult (see “How to remove NEXPLANON®” below and
“WARNINGS AND PRECAUTIONS”).
The NEXPLANON® implant should be inserted subdermally just under the skin at the inner side of the
non-dominant upper arm. The insertion site is overlying the triceps muscle about 8-10 cm (3-4 inches) from the medial epicondyle of the humerus and 3-5 cm (1.25-2 inches) posterior to (below) the sulcus (groove) between the biceps and triceps muscles. This location is intended to avoid the large blood vessels and nerves lying within and surrounding the sulcus (see Figures 2a and 2b).
Immediately after insertion, the presence of the implant should be verified by palpation. Both the HCP and the woman should be able to feel the implant under the skin after placement. In case the implant cannot be palpated or when the presence of the implant is doubtful, see “How to insert NEXPLANON®”. The HCP should instruct the woman on how to continue to verify the presence of the implant by having her gently palpate the site occasionally.
The NEXPLANON® package contains a Patient Alert Card intended for the woman which records the
batch number of the implant. HCPs are requested to record the date of insertion, the arm of insertion and the intended day of removal on the Patient Alert Card. The card provides a warning for the woman to contact her HCP as soon as possible if she is unable to feel the implant. The package also includes adhesive labels intended for HCP records showing the batch number.
When to insert NEXPLANON®
IMPORTANT: Pregnancy should be ruled out 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:
The implant 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®
Changing from a combined hormonal contraceptive method (combined oral contraceptive (COC), vaginal ring or transdermal patch)
The implant should be inserted preferably on the day after the last active tablet (the last tablet containing the active substances) of the previous COC, but at the latest on the day following the usual tablet-free or placebo tablet interval of the previous COC. In case a vaginal ring or transdermal patch has been used, the implant should be inserted preferably on the day of removal, but at the latest when the next application would have been due.
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.
Changing from a progestin-only contraceptive method (progestin-only pill, injectable, implant or intrauterine system (IUS))
As there are several types of progestin-only methods, the insertion of the implant must be performed as follows:
Injectable Contraceptives: Insert the implant on the day the next injection is due. Progestin-only pill: A woman may switch from the progestin-only pill to NEXPLANON® on
any day of the month. The implant should be inserted within 24 hours after taking the last tablet.
Implant/Intrauterine system (IUS): Insert the implant on the same day the previous 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: The implant should be inserted within 5 days following a first trimester abortion or miscarriage.
Second trimester: Insert the implant 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:
Breast-feeding: The implant should be inserted after the fourth postpartum week (see WARNINGS AND PRECAUTIONS/Special Populations/Pregnant Women and
Breast-feeding). The woman should be advised to use a barrier method until 7 days after insertion. If intercourse has already occurred, pregnancy should be excluded.
Not breast-feeding: The implant should be inserted between 21 to 28 days postpartum. If inserted as recommended, back-up contraception is not necessary. If the implant is inserted later than 28 days postpartum, the woman should be advised to use a barrier method until 7 days after insertion. If intercourse has already occurred, pregnancy should be excluded.
How to insert NEXPLANON®
The basis for successful use and subsequent removal of the NEXPLANON® implant is a correct and carefully performed subdermal insertion of the implant in the non-dominant arm in accordance with the instructions. Both the HCP and the woman should be able to feel the implant under the woman’s skin after placement.
The implant should be inserted subdermally just under the skin at the inner side of the non-dominant upper arm.
An implant inserted more deeply than subdermally (deep insertion) may not be palpable and the localization and/or removal can be difficult (see “How to remove NEXPLANON®” and “WARNINGS AND PRECAUTIONS”).
If the implant is inserted deeply, neural or vascular damage may occur. Deep or incorrect insertions have been associated with paresthesia (due to neural damage) and migration of the implant (due to intramuscular or fascial insertion), and in rare cases with intravascular
insertion.
Insertion of NEXPLANON® should be performed under aseptic conditions and only by a qualified HCP
who is familiar with the procedure. Insertion of the implant should only be performed with the preloaded applicator.
Insertion Procedure
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
To help make sure the implant is inserted just under the skin, the HCP 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.
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). This position deflects the ulnar nerve away from the insertion site.
[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 muscle (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.
Step 3. Make two marks with a surgical marker: first, mark the spot where the 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.
Cross section of the upper left arm, as viewed from the elbow Medial (inner side of the arm) Lateral (outer side of the arm)
[Figure 2a] [Figure 2b] [Figure 2c]
P, proximal (toward the shoulder); D, distal (toward 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 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 you have fully inserted the needle subdermally, as doing so will retract the needle and release the implant from the applicator.
[Figure 3]
Step 9. If the purple slider is released prematurely, restart the procedure with a new applicator.
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).
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 you can clearly see the insertion site and the movement of the needle just under the skin (see Figure 6).
[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. 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.
[Figure 7]
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 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 section below “If the rod is not palpable after
insertion”.
[Figure 9] Step 18. Request that the woman palpate the implant.
Step 19. Apply sterile gauze with a pressure bandage to minimize bruising. The woman may remove the pressure bandage in 24 hours and the small adhesive bandage over the insertion site after 3-5 days.
Step 20. Complete the Patient Alert Card and give it to the woman to keep. Also, complete the adhesive labels and affix it to the woman's medical record.
Step 21. The applicator is for single use only and must be adequately disposed of, in accordance with local regulations for the handling of biohazardous waste.
If the rod is not palpable after insertion:
If you cannot palpate 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, 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. In case these imaging methods fail, it is advised to verify the presence of the implant by measuring the etonogestrel level in a blood sample from the women. In this case the Organon Canada office (which can be reached at 1-844-820-5468) will provide the appropriate protocol.
Until you have verified the presence of the implant, the woman must use a non-hormonal contraceptive method.
Deeply-placed implants should be localized and removed as soon as possible to avoid the potential for distant migration.
How to remove NEXPLANON®
Removal of the implant should only be performed under aseptic conditions by a HCP who is familiar with the removal technique. If you are unfamiliar with the removal technique, contact Organon Canada at 1-844-820-5468 for further information.
Before initiating the removal procedure, the HCP should assess the location of the implant. Verify the exact location of the implant in the arm by palpation.
If the implant is not palpable, consult the Patient Alert 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 an HCP experienced in removing deeply placed implants and familiar with localizing the implant and the anatomy of the arm. Contact Organon Canada at 1-844-820-5468 for further
information.
See section below on “Localization and removal of a non-palpable implant” if the implant cannot be palpated.
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)
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) This position deflects the ulnar nerve away from the removal site.
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. Contact Organon Canada at 1-844-820-5468 for further information.
[Figure 10]
P, proximal (toward the shoulder); D, distal (toward the elbow)
Mark the distal end (end closest to the elbow), for example, with a surgical marker.
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 can 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).
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 an HCP experienced with complex removals or contact Organon Canada at 1-844-820-5468.
[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 "How to remove NEXPLANON®". 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 “How to replace NEXPLANON®”).
Step 10. After removing the implant, close the incision with a sterile adhesive wound closure.
Step 11. Apply sterile gauze with a pressure bandage to minimize bruising. The woman may
remove the pressure bandage after 24 hours and the sterile adhesive wound closure after 3-5 days.
Localization and removal of a non-palpable implant
There have been occasional reports of migration of the implant; usually this involves minor movement relative to the original position, but it may lead to the implant not being palpable at the location in which it was placed (see “WARNINGS AND PRECAUTIONS”). 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 an HCP 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 rare 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; HCPs 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. Please contact Organon Canada at 1-844-820-5468 for further guidance.
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 damage to deeper neural or vascular structures in the arm. Non-palpable and deeply inserted implants should be removed by HCPs 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 not recommended. Please contact Organon Canada at 1-844-820-5468 for further guidance.
How to replace NEXPLANON®
Immediate replacement can be done after removal of the previous implant and is similar to the insertion procedure described in “How to insert NEXPLANON®” (See DOSAGE AND ADMINISTRATION).
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, i.e., 8-10 cm from the medial epicondyle of the humerus and 3-5 cm posterior to (below) the sulcus (see “How to insert NEXPLANON®”). If the same incision is being used to insert a new implant, anaesthetize the insertion site (e.g., 2 mL lidocaine (1%)) applied just under the skin
commencing at the removal incision along the ‘insertion canal’ and follow the subsequent steps in the insertion instructions.
5
OVERDOSAGE
An implant should always be removed before inserting a new one. There are no data available on overdose with etonogestrel. There have been no reports of serious deleterious effects from an overdose of contraceptives in general.
For management of a suspected drug overdose, contact your regional poison control centre.
6
DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
Table – Dosage Forms, Strengths, Composition and PackagingRoute of Administration
Dosage Form /
Strength/Composition Non-medicinal Ingredients
subdermal Implant / 68 mg /
radiopaque,
non-Implant core
NEXPLANON® (etonogestrel extended release subdermal implant) is a non-uterine, long-acting reversible contraceptive (LARC). NEXPLANON® consists of a radiopaque, non-biodegradable, soft, progestin-only flexible implant rod. Each radiopaque implant contains 68 mg of etonogestrel. After insertion into the arm, NEXPLANON® releases etonogestrel continuously for up to 3 years.
NEXPLANON® does not contain estrogen. The release rate is approximately 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 to approximately 25-30 mcg/day at the end of the third year. The innovative applicator is designed to be operated with one hand and to help facilitate correct subdermal insertion of the implant.
Packaging
The pack contains one implant (4 cm in length and 2 mm in diameter) which is preloaded in the stainless-steel needle of a ready-for-use, disposable, sterile applicator. The applicator containing the implant is packed in a blister pack made of transparent polyethyleneterephtalate glycol (PETG) sealed with an EVA coated spunbonded High Density Polyethylene (HDPE) lidding film. The blister pack is packed in a box together with the package leaflet.
Figure 19: NEXPLANON® applicator
7
WARNINGS AND PRECAUTIONS
Please see the Serious Warnings and Precautions Box at the beginning of Part I: Health Professional Information.
General
If any of the conditions / risk factors described below are present, the benefits of progestin use should biodegradable, white to
off-white, soft, progestin-only flexible implant rod preloaded in a sterile, disposable applicator with a length of 4 cm and 2 mm in diameter
copolymer (28% vinyl acetate, 43 mg), magnesium stearate (0.1 mg).
Implant skin
Ethylene vinyl acetate copolymer (15% vinyl acetate, 15 mg)
be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start with NEXPLANON®. In the event of aggravation, exacerbation or first appearance of any of these conditions, the woman should contact her HCP. The HCP should then decide if use of NEXPLANON® should be discontinued.
Complications of Insertion and Removal
NEXPLANON® should be inserted subdermally so that it will be palpable after insertion, and this should be confirmed by palpation immediately after insertion. Failure to insert NEXPLANON® properly may go unnoticed unless it is palpated immediately after insertion. Undetected failure to insert the implant may lead to an unintended pregnancy. Complications related to insertion and removal procedures, such as pain, paresthesias, bleeding, hematoma, scarring or infection, may occur.
If NEXPLANON® is inserted deeply (intramuscular or in the fascia), neural or vascular injury may occur. To help reduce the risk of neural or vascular injury, NEXPLANON® should be inserted subdermally just under the skin at the inner side of the non-dominant upper arm overlying the triceps muscle about 8-10 cm (3-4 inches) from the medial epicondyle of the humerus and 3-5 cm (1.25-2 inches) posterior to 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. Deep insertions of NEXPLANON® 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 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 or surgical procedures may be needed for removal. Some cases of implants found within the pulmonary artery were associated with chest pain and/or respiratory disorders (such as dyspnea, cough, or
hemoptysis); others were asymptomatic.
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 the menstrual bleeding pattern
pattern. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration. In clinical trials of the non-radiopaque etonogestrel implant (IMPLANON), 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 NEXPLANON® use is broadly predictive of 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. Also see 8.2 Clinical Trial Adverse Reactions.
Broken or bent implant
.There have been reports of broken or bent implants, which may be related to external forces (e.g. manipulation of the implant, tourniquet use at the implant site or trauma to the implant site during contact sports) while in the patient’s arm. There have also been reports of migration of a broken implant fragment within the arm. Based on in vitro data, when the implant is broken or bent, the release rate of etonogestrel may be slightly increased, which is not expected to have clinically meaningful effects. When an implant is removed, it is important to remove it in its entirety.
Medical examination/consultation
Prior to the initiation or reinstitution of NEXPLANON® a complete medical history (including family medical history) should be taken and pregnancy should be excluded. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications (see CONTRAINDICATIONS) and warnings (see WARNINGS AND PREAUTIONS). It is recommended that the woman returns for a medical up three months after insertion of NEXPLANON®. During this check-up, the blood pressure should be measured and an enquiry should be made after any questions, complaints or the occurrence of undesirable effects. The frequency and nature of further periodic checks should be adapted to the individual woman, guided by clinical judgement. Women should be advised that NEXPLANON® does not protect against HIV (AIDS) and other sexually transmitted diseases.
Other Conditions
The following other conditions not described below have been reported both during pregnancy and during sex steroid use, but an association with the use of progestins has not been established: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss and (hereditary) angioedema.
Reduced efficacy with concomitant medications
The efficacy of NEXPLANON® may be reduced when concomitant medications that decrease the plasma concentration of etonogestrel are used (see DRUG INTERACTIONS).
Carcinogenesis and Mutagenesis
Carcinoma of the Breast and Reproductive Organs
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 these 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.
Cardiovascular
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 NEXPLANON® can be considered. Women with hypertension using NEXPLANON® should be closely monitored. If a sustained hypertension develops during the use of NEXPLANON®, or if a significant increase in blood pressure does not adequately respond to antihypertensive therapy, NEXPLANON® should be removed.
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). NEXPLANON® 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 etonogestrel implants. NEXPLANON® should be removed in the event of a thrombosis.
Due to the risk of thromboembolism associated with pregnancy and immediately following delivery, NEXPLANON® 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 NEXPLANON® implant in case of long-term immobilization due to surgery or illness.
Driving and Operating Machinery No observed effects.
Endocrine and Metabolism
Carbohydrate and Lipid Metabolic Effects
Use of NEXPLANON® may induce mild insulin resistance and small changes in glucose concentrations of unknown clinical significance. Carefully monitor prediabetic and diabetic women using NEXPLANON®. Women who are being treated for hyperlipidemia should be followed closely if they elect to use NEXPLANON®. Some progestins may elevate LDL levels and may render the control of hyperlipidemia more difficult.
Weight Gain
In clinical studies, mean weight gain in U.S. non-radiopaque etonogestrel implant (IMPLANON) users was 2.8 pounds after one year and 3.7 pounds after two years. How much of the weight gain was related to the non-radiopaque etonogestrel implant is unknown. In studies, 2.3% of the users reported weight gain as the reason for having the non-radiopaque etonogestrel implant removed.
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 NEXPLANON® causes fluid retention.
Genitourinary Ectopic Pregnancy
As with all progestin-only contraceptive products, be alert to the possibility of an ectopic pregnancy among women using NEXPLANON® who become pregnant or complain of lower abdominal pain. Although ectopic pregnancies are uncommon among women using NEXPLANON®, a pregnancy that occurs in a woman using NEXPLANON® may be more likely to be ectopic than a pregnancy occurring in a woman using no contraception.
Ovarian Cysts
With all low-dose hormonal contraceptives, follicular development may occur and occasionally the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally, these enlarged follicles disappear spontaneously. Often, they are asymptomatic; in some cases, they are associated with mild abdominal pain. They rarely require surgical intervention.
Hepatic/Biliary/Pancreatic Liver Disease
Disturbances of liver function may necessitate the discontinuation of hormonal contraceptive use until markers of liver function return to normal. Remove NEXPLANON® 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 NEXPLANON®.
The progestin in NEXPLANON® may be poorly metabolized in women with liver impairment. Use of NEXPLANON® in women with active liver disease or liver cancer is contraindicated (see
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 NEXPLANON®.
Monitoring and Laboratory Tests Laboratory parameters
Data obtained with combined OCs have shown that contraceptive steroids may affect some laboratory parameters, including biochemical parameters of liver, thyroid, adrenal and renal function, serum levels of (carrier) proteins, e.g., corticosteroid binding globulin and lipid/lipoprotein fractions,
parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. The changes generally remain within the normal range. To what extent this also applies to progestin-only
contraceptives is unknown.
Sex hormone-binding globulin concentrations may be decreased for the first six months after
NEXPLANON® insertion followed by gradual recovery. Thyroxine concentrations may initially be slightly decreased followed by gradual recovery to baseline.
Ophthalmologic Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
Peri-Operative Considerations
Removal of the implant should also be considered in case of long-term immobilization due to surgery or illness (see Cardiovascular).
Psychiatric Depressed Mood
Women with a history of depressed mood should be carefully observed. Consideration should be given to removing NEXPLANON® in patients who become significantly depressed.
Sexual Health 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.
Skin Chloasma
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst using NEXPLANON®.
7.1 Special Populations 7.1.1 Pregnant Women
NEXPLANON® is contraindicated during pregnancy because there is no need for pregnancy prevention in a woman who is already pregnant (see Contraindications). 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 combined hormonal
contraceptives (CHCs) prior to conception or during early pregnancy. NEXPLANON® should be removed if maintaining a pregnancy. Also see NON-CLINICAL TOXICOLOGY.
7.1.2 Breast-feeding
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. 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.
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.
7.1.3 Pediatrics
Safety and efficacy of NEXPLANON® have been established in women of reproductive age and are expected to be the same for post pubertal 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.
7.1.4 Geriatrics
NEXPLANON® is not indicated for postmenopausal women. This product has not been studied in women over 65 years of age and is not indicated in this population.
Overweight Women
The effectiveness of the etonogestrel implant in women who weighed more than 130% of their ideal body weight has not been defined because such women were not studied in clinical trials. Serum concentrations of etonogestrel are inversely related to body weight and decrease with time after implant insertion. It is therefore possible that NEXPLANON® may be less effective in overweight women, especially in the presence of other factors that decrease serum etonogestrel concentrations such as concomitant use of hepatic enzyme inducers.
8
ADVERSE REACTIONS
8.1 Adverse Reaction OverviewIn women using (combined oral) contraceptives a number of (serious) undesirable effects have been reported. These include venous thromboembolic disorders, arterial thromboembolic disorders, hormone dependent tumours (e.g., liver tumours, breast cancer) and chloasma (see WARNINGS AND PRECAUTIONS).
The adverse reactions reported with the use of implants are discussed elsewhere in the Product Monograph:
• Ectopic Pregnancies (see Warnings and Precautions)
• Thrombotic and Other Vascular Events (see Warnings and Precautions) • Complications of Insertion and Removal (see Warnings and Precautions) • In situ Broken or Bent Implant (see Warnings and Precautions)
8.2 Clinical Trial Adverse Reactions
Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful in identifying drug-related adverse events and for approximating rates.
The safety assessment of the clinical studies was performed using a non-radiopaque implant on a total of 942 subjects. Data was accumulated from 11 clinical trials which are detailed in PART II (see
CLINICAL TRIALS).
During the use of NEXPLANON®, women are likely to have changes in their menstrual bleeding pattern.
These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration. Amenorrhea was reported in about 1 of 5 women while another 1 of 5 women reported frequent and/or prolonged bleeding. Occasionally, heavy bleeding has been reported. In clinical trials, bleeding changes were the most common reason for stopping treatment (about 11 %). Dysmenorrhea tended to improve while using NEXPLANON®. The bleeding pattern
experienced during the first three months is broadly predictive of future bleeding patterns for many women.
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 nonradiopaque etonogestrel implant are shown in Table 2 .
Table 2: Percentages of Patients With 0, 1-7, 8-21, or >21 Days of Spotting or Bleeding Over a 90-Day Interval While Using the Non-Radiopaque Etonogestrel Implant (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 the non-radiopaque etonogestrel implant for up to 2
years, and the proportion of 90-day intervals with these bleeding patterns, are summarized in Table 3.
Table 3: Bleeding Patterns Using the Non-Radiopaque Etonogestrel Implant (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 3315 recording periods of 90 days 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.
Adverse reactions that resulted in a rate of discontinuation of ≥1% are shown in Table 4.
Table 4: Adverse Reactions Leading to Discontinuation of Treatment in 1% or More of Subjects in Clinical Trials of the Non-Radiopaque Etonogestrel Implant (IMPLANON)
Adverse Reactions All Studies
N = 942 Bleeding Irregularities* 11.1% Emotional Lability† 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.
The most frequently occurring treatment related individual Adverse Events were headache (15.5%), weight increase (12.0%), acne (11.8%), breast pain (10.2%), emotional lability (5.8%) and abdominal pain (5.2%).
Table 5: Drug-related Adverse Events with a causal relation to study medication (defined as possibly, probably, or definitely related to study drug according to the investigator) with an incidence of ≥1% in subjects treated with the non-radiopaque etonogestrel implant*
Number of Subjects (n=942) n % Gastro-intestinal disorders abdominal pain 49 5.2 flatulence 29 3.1 nausea 24 2.5
General disorders and administration site conditions
insertion site pain 45 4.8
insertion site reaction 33 3.5
fatigue 15 1.6
influenza-like symptoms 10 1.1
pyrexia 17 1.8
pain 23 2.4
edema 16 1.7
Infections and Infestations
vaginitis 13 1.4
Investigations
weight decrease 24 2.5
weight increase 113 12
Metabolism & nutritional disorders
appetite increased 13 1.4
Musculoskeletal and connective tissue disorders
back pain 10 1.1
Nervous system disorders
headache 146 15.5 dizziness 46 4.9 Psychiatric disorders depression 33 3.5 emotional Lability 55 5.8 libido decreased 23 2.4 anxiety 12 1.3 nervousness 33 3.5
Reproductive system and breast disorders
breast pain 96 10.2
dysmenorrhea 41 4.4
abnormal sexual function 16 1.7
leukorrhea 10 1.1
ovarian cyst 24 2.5
Skin and subcutaneous disorders
acne 111 11.8
rash 9 1.0
alopecia 22 2.3
Vascular disorders
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.
8.3 Less Common Clinical Trial Adverse Reactions Gastrointestinal disorders: vomiting, constipation, diarrhea Immune System disorders: hypersensitivity
Infections and Infestations: pharyngitis, rhinitis, urinary tract infection
Musculoskeletal and connective tissue disorders: arthralgia, myalgia, musculoskeletal pain Nervous System disorders: migraine, somnolence
Psychiatric disorders: insomnia Renal and urinary disorders: dysuria
Reproductive system and breast disorders: vulvovaginal discomfort, galactorrhea, breast enlargement, pruritis genital
Skin and subcutaneous disorders: hypertrichosis, pruritus
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Changes in laboratory values have not been studied during clinical trials with NEXPLANON®
(see WARNINGS AND PRECAUTIONS/Monitoring and Laboratory Tests).
8.5 Post-Market Adverse Reactions
During postmarketing surveillance, a clinically relevant rise in blood pressure has been observed in rare cases. Seborrhoea has also been reported. Anaphylactic reactions, urticaria, angioedema, aggravation of angioedema and/or aggravation of hereditary angioedema may occur.
Insertion or removal of the implant may cause some bruising, slight local irritation, pain or itching. Fibrosis at the implant site may occur, a scar may be formed or an abscess may develop. Paresthesia or paresthesia-like events may occur. Expulsion or migration of the implant have been reported, including rarely to the chest wall. In rare 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 respiratory disorders (such as dyspnea, cough or hemoptysis); others have been reported as asymptomatic (see WARNINGS AND PRECAUTIONS). Surgical intervention might be necessary when removing the implant.
On rare occasions, ectopic pregnancies have been reported (see WARNINGS AND PRECAUTIONS).
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.
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.
9
DRUG INTERACTIONS
9.2 Drug Interactions OverviewThe prescribing information of concomitant medications should be consulted to identify potential interactions.
9.4 Drug-Drug Interactions
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Effects of other medicinal products on NEXPLANON®
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.
Effects of NEXPLANON® on other medicinal products
Hormonal contraceptives may affect the metabolism of other drugs. Consequently, plasma concentrations may either increase (e.g., cyclosporine) or decrease (e.g., lamotrigine). Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
9.5 Drug-Food Interactions
Interactions with food are not expected for the subdermally administered NEXPLANON®.
9.6 Drug-Herb InteractionsInteractions with the herbal remedy St. Johns wort can occur (see Drug-Drug Interactions
above).
9.7 Drug-Laboratory Test Interactions
Data obtained with combined OCs have shown that contraceptive steroids may affect some laboratory parameters, including biochemical parameters of liver, thyroid, adrenal and renal function, serum levels of (carrier) proteins, e.g., corticosteroid binding globulin and lipid/lipoprotein fractions,
parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. The changes generally remain within the normal range. To what extent this also applies to progestin-only
contraceptives is not known.
Drug-Lifestyle Interactions
On the basis of the pharmacodynamic profile, NEXPLANON® is expected to have no influence on the ability to drive or use machines.
10 CLINICAL PHARMACOLOGY
10.1 Mechanism of ActionEtonogestrel is the biologically active metabolite of desogestrel, a progestin widely used in oral contraceptives (OCs). It is structurally derived from 19-nortestosterone and binds with high affinity to progesterone receptors in the target organs. The contraceptive effect of etonogestrel is primarily
achieved by inhibition of ovulation. Ovulations were not observed in the first two years of use of the implant and only rarely in the third year. Besides inhibition of ovulation, etonogestrel also causes changes in the cervical mucus, which hinders the passage of spermatozoa.
10.2 Pharmacodynamics
Exposure-response relationships of NEXPLANON® are unknown.
10.3 Pharmacokinetics Absorption
After subdermal insertion of the etonogestrel implant, etonogestrel is released into the circulation and is approximately 100% bioavailable.
In a three year clinical trial, NEXPLANON® and the non-radiopaque etonogestrel implant (IMPLANON)
yielded comparable systemic exposure to etonogestrel. For NEXPLANON®, the mean (± SD) maximum
serum etonogestrel concentrations were 1200 (± 604) pg/mL and were reached within the first two weeks after insertion (n=50). The mean (± SD) serum etonogestrel concentration decreased gradually over time, declining to 202 (± 55) pg/mL at 12 months (n=41), 164 (± 58) pg/mL at 24 months (n=37), and 138 (± 43) pg/mL at 36 months (n=32). For the non-radiopaque etonogestrel implant (IMPLANON), the mean (± SD) maximum serum etonogestrel concentrations were 1145 (± 577) pg/mL and were reached within the first two weeks after insertion (n=53). The mean (± SD) serum etonogestrel
concentration decreased gradually over time, declining to 223 (± 73) pg/mL at 12 months (n=40), 172 (± 77) pg/mL at 24 months (n=32), and 153 (± 52) pg/mL at 36 months (n=30).
Figure 20: 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.
Elimination
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.
Special Populations and Conditions
Pediatrics: Safety and efficacy of NEXPLANON® have been established in women of
reproductive age and are expected to be the same for post pubertal 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 (see INDICATIONS).
Geriatrics: NEXPLANON® is not indicated for postmenopausal women (see INDICATIONS) Sex: NEXPLANON® is indicated for prevention of pregnancy in women aged 18 years or older
