Implanon nXT™: product monograph
Table of Contents
Part I: Health Care Professional Information
2-19
Summary Product Information
1
2
3
2
Indication
4.1
3
Posology and Administration
4.2
3-10
Contraindications
4.3
10
Warnings and Precautions
4.4
10-12
Drug Interactions
4.5
13
Pregnancy and Lactation
4.6
13-14
Adverse Effects
4.8
14-16
Overdose
4.9
16
Pharmacodynamic Properties
5.1
16-17
Pharmacokinetic Properties
5.2
17
Preclinical Safety Data
5.3
18
Pharmaceutical Particulars
6
18
Storage and Handling
6.4
-
6.6
18
Part II: Select Clinical Trials
21-31
Bioequivalence
21
Tolerability and Clinical Safety
24
Management of Bleeding Patterns
26
Clinician Satisfaction
29
References
31
1
Name of the
Medicinal
Product
IMPlanon nXT, 68 mg etonogestrel implant for subdermal use
2
Qualitative and
Quantitative
Composition
IMPlanon nXT is a radiopaque, non-biodegradable, progestogen-only, flexible implant preloaded in a sterile, ready-for-use, disposable applicator.Each radiopaque implant contains 68 mg of etonogestrel; the release rate is approximately 60-70 µg/day in weeks 5-6 and has decreased to approximately 35-45 µg/day at the end of the first year, to approximately 30-40 µg/day at the end of the second year and to approximately 25-30 µg/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.
For a full list of excipients, see section 6.1 “list of excipients”.
3
Pharmaceutical
Form
Implant for subdermal use Radiopaque, non-biodegradable, white to off-white, soft, flexible rod with a length of 4 cm and 2 mm in diameter.
Implanon nXT™: product monograph
part I: Health Care professional Information
4
Clinical Particulars
4.1
Therapeutic indication
Contraception.
4.2
Posology and method of administration
Pregnancy should be excluded before insertion of IMPLANON NXT.
Healthcare professionals (HCPs) are strongly recommended to participate in a training session to become familiar with the use of the IMPlanon nXT applicator and techniques for insertion and removal of the IMPlanon nXT implant and where appropriate, request supervision prior to inserting or removing the implant.
additional information and more detailed instructions concerning the insertion and removal of the implant will be sent on request free of charge Please contact MSD Office at (632) 784-9500
Prior to inserting the implant, carefully read and follow the instructions for insertion and removal of the implant in section 4.2.3 “How to insert IMPlanon nXT” and section 4.2.4 “How to remove IMPlanon nXT”.
4.2.1
How to use IMPlanon nXT
IMPlanon nXT is a long-acting hormonal contraceptive. 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. HCPs may consider earlier replacement of the implant in heavier women (see section 4.4.1 “Warnings”). 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 IMPlanon nXT, but wants to continue preventing pregnancy, another contraceptive method should be recommended.
The basis for successful use and subsequent removal of the IMPlanon nXT 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 (section 4.2.2 “When to insert IMPLANON NXT” and 4.2.3 “How to insert IMPLANON NXT), and on the correct day, this may result in an unintended pregnancy.
The IMPlanon nXT implant should be inserted subdermally just under the skin at the inner side of the
upper arm to avoid the large blood vessels and nerves that lie deeper in the connective tissue between the biceps and triceps muscles.
Immediately after insertion, the presence of the implant should be verified by palpation. In case the implant cannot be palpated or when the presence of the implant is doubtful, other methods must be applied to confirm its presence (see section 4.2.3 “How to insert IMPlanon nXT”). Until the presence of the implant has been verified, the woman should be advised to use a non-hormonal contraceptive method.
The IMPlanon nXT package contains a User 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 User Card. The package also includes adhesive labels intended for HCP records showing the batch number.
4.2.1
4
-4.2.2
When to insert IMPlanon nXT
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 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 Implanon nXT
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 progestagen-only contraceptive method (e.g. progestagen-only pill, injectable, implant, or intrauterine system [IUS])
as there are several types of progestagen-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.
• Progestagen-only pill: a woman may switch from the progestagen-only pill to IMPlanon nXT 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.
Guiding Mark Insertion Site 8-10 cm Medial Epicondyle
Implanon nXT™: product monograph
part I: Health Care professional Information
4.2.3
How to insert IMPlanon nXT
The basis for successful use and subsequent removal of IMPlanon nXT 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. If the implant is inserted too deep, neural or vascular damage may occur. Too 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. Moreover, when the implant is inserted too deep, it may not be palpable and the localization and/or removal can be difficult.
Insertion of IMPlanon nXT 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.
It is recommended that the HCP is in a seated position during the entire insertion procedure so that the insertion site and the movement of the needle just under the skin can be clearly seen from the side.
• Have the woman lie on her back on the examination table with her non-dominant arm flexed at the elbow and externally rotated so that her wrist is parallel to her ear or her hand is positioned next to her head (Figure 1).
• Make two marks with a sterile marker: first, mark the spot where the implant will be inserted, and second, mark a spot a few centimeters proximal to the first mark (Figure 2). This second mark will later serve as a direction guide during insertion.
• Identify the insertion site, which is at the inner side of the non-dominant upper arm about 8-10 cm (3-4 inches) above the medial epicondyle of the humerus (Figure 2). The implant should be inserted subdermally just under the skin to avoid the large blood vessels and nerves that lie deeper in the subcutaneous tissue in the sulcus between the triceps and biceps muscles (see section 4.4.1 “Warnings”).
4.2.3
• Clean the insertion site with an antiseptic solution.
• 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).
• Remove the sterile preloaded disposable IMPlanon nXT applicator carrying the implant from its blister. The applicator should not be used if sterility is in question.
Figure 1
Purple Slider
Figure 3
Figure 4
Figure 5 • 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 may see the white colored implant by looking into the tip of the needle. Do not touch the purple slider until you have fully inserted the needle subdermally, as it will retract the needle and prematurely release the implant from the applicator.
• Lower the applicator to a horizontal position. While lifting the skin with the tip of the needle (Figure 6), slide the needle to its full length. You may feel slight resistance but do not exert excessive force. If the needle is not inserted to its full length, the implant will not be inserted properly.
You can best see movement of the needle if you are seated and are looking at the applicator from the side and NOT from above. In this position, you can clearly see the insertion site and the movement of the needle just under the skin.
• With your free hand, stretch the skin around the insertion site with thumb and index finger (Figure 4).
• Puncture the skin with the tip of the needle angled about 30° (Figure 5).
Implanon nXT™: product monograph
part I: Health Care professional Information
Figure 7
Figure 8 • Keep the applicator in the same position with the needle inserted
to its full length. If needed, you may use your free hand to keep the applicator in the same position during the following procedure. Unlock the purple slider by pushing it slightly down. Move the slider fully back until it stops (Figure 7). The implant is now in its final subdermal position, and the needle is locked inside the body of the applicator. The applicator can now be removed.
If the applicator is not kept in the same position during this procedure or if the purple slider is not completely moved to the back, the implant will not be inserted properly.
• Always verify the presence of the implant in the woman’s arm immediately after insertion by palpation. By palpating
both ends of the implant, you should be able to confirm the presence of the 4 cm rod (Figure 8).
If you cannot feel the implant or are in doubt of its presence,
• 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. Suitable methods 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). Prior to the application of X-ray CT, USS or MRI for the localization of the implant, it is recommended to consult the local supplier of IMPlanon nXT for instructions. 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 of the subject. In this case the local supplier will provide the appropriate procedure. Until you have verified the presence of the implant, a non-hormonal contraceptive method must be used.
• Apply a small adhesive bandage over the insertion site. Request that the woman palpate the implant.
• Apply sterile gauze with a pressure bandage to minimize bruising. The woman may remove the pressure bandage in 24 hours and the small bandage over the insertion site after 3-5 days.
• Complete the User Card and give it to the woman to keep. Also, complete the adhesive labels and affix it to the woman’s medical record.
• The applicator is for single use only and must be adequately disposed of, in accordance with local regulations for the handling of biohazardous waste.
4.2.4
How to remove IMPlanon nXT
Before initiating the removal procedure, the HCP should consult the User Card for the location of the IMPlanon nXT implant. Verify the exact location of the implant in the arm by palpation.
If the implant is not palpable, two-dimensional X-ray can be performed to verify its presence. a non-palpable implant should always be first located prior to removal. Suitable methods for localization include, X-ray computer tomography (CT), ultrasound scanning (USS) with a high-frequency linear array transducer (10 MHZ or greater) or magnetic resonance imaging (MRI). If 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 your local supplier for further guidance.
after localization of a non-palpable implant, consider conducting removal with ultrasound guidance.
There have been occasional reports of migration of the implant; usually this involves minor movement relative to the original position unless inserted too deeply (see also section 4.4.1 “Warnings”). This may complicate localization of the implant by palpation, USS and/or MRI, and removal may require a larger incision and more time.
Removal of the implant should only be performed under aseptic conditions by a HCP who is familiar with the removal technique.
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 damage to deeper neural or vascular structures in the arm and should be performed by HCPs familiar with the anatomy of the arm.
If the implant cannot be removed, please contact your local supplier for further guidance.
Figure 9 • Clean the site where the incision will be made and apply an
antiseptic. locate the implant by palpation and mark the distal end (end closest to the elbow), for example, with a sterile marker (Figure 9).
• Anesthetize the arm, for example, with 0.5 to 1 ml 1% lidocaine at the marked site where the incision will be made (Figure 10). Be sure to inject the local anesthetic under the implant to keep it close to the skin surface.
Implanon nXT™: product monograph
part I: Health Care professional Information
4.2.4
Figure 12
Figure 13 Figure 14
• Push down the proximal end of the implant (Figure 11) to stabilize it; a bulge may appear indicating the distal end of implant. Starting at the distal tip of the implant, make a longitudinal incision of 2 mm towards the elbow.
• Gently push the implant towards the incision until the tip is visible. Grasp the implant with forceps (preferably curved mosquito forceps) and remove the implant (Figure 12).
• If the implant is encapsulated, make an incision into the tissue sheath and then remove the implant with the forceps (Figures 13 and 14).
Figure 15 Figure 16 Figure 17
• If the tip of the implant does not become visible in the incision, gently insert a forceps into the incision (Figure 15). Flip the forceps over into your other hand (Figure 16). With a second pair of forceps carefully dissect the tissue around the implant and grasp the implant (Figure 17). The implant can then be removed.
4.2.5
How to replace IMPlanon nXT
Immediate replacement can be done after removal of the previous implant and is similar to the insertion procedure described in section 4.2.3 “How to insert IMPlanon nXT”.
The new implant may be inserted in the same arm, and through the same incision from which the previous
implant was removed. If the same incision is being used to insert a new implant, anesthetize the insertion site (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.
4.3
Contraindications
Progestagen-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 IMPlanon nXT, the product should be stopped immediately.
• Known or suspected pregnancy. • Active venous thromboembolic disorder.
• Known or suspected sex steroid sensitive malignancies.
• Presence or history of liver tumours (benign or malignant). • Presence or history of severe hepatic disease as long as
liver function values have not returned to normal. • Undiagnosed vaginal bleeding.
• Hypersensitivity to the active substance or to any of the excipients of IMPlanon nXT.
4.4
Special warnings and special precautions for use
4.4.1
Warnings
If any of the conditions / risk factors mentioned below is present, the benefits of progestagen use should be weighed against the possible risks for each individual
these conditions, the woman should contact her HCP. The HCP should then decide on whether the use of IMPlanon nXT should be discontinued.
• Confirm that the entire implant, which is 4 cm long, has been removed by measuring its length. If a partial implant (less than 4 cm) is removed, the remaining piece should be removed by following the instructions in section 4.2.4 “How to remove IMPlanon nXT”.
• If the woman would like to continue using IMPlanon nXT, a new implant may be inserted immediately after the old implant is removed using the same incision (Section 4.2.5 “How to replace IMPlanon nXT”). • After removing the implant, close the incision with a steri-strip and apply an adhesive bandage.
• Apply sterile gauze with a pressure bandage to minimize bruising. The woman may remove the pressure bandage after 24 hours and the small bandage after 3-5 days.
Implanon nXT™: product monograph
part I: Health Care professional Information
diagnosed is slightly increased. This increased risk disappears gradually within 10 years after discontinuation of oC use and is not related to the duration of use, but to the age of the woman when using the oC. The expected number of cases diagnosed per 10 000 women who use combined oCs (up to 10 years after stopping) relative to never users over the same period have been calculated for the respective age groups to be: 4.5/4 (16-19 years), 17.5/16 (20-24 years), 48.7/44 (25-29 years), 110/100 (30-34 years), 180/160 (35-39 years) and 260/230 (40-44 years). The risk in users of contraceptive methods, which only contain progestagens, is possibly of similar magnitude as that associated with combined oCs. However, for these methods, the evidence is less conclusive. Compared to the risk of getting breast cancer ever in life, the increased risk associated with oCs is low. The cases of breast cancer diagnosed in oC users tend to be less advanced than in those who have not used oCs. The increased risk observed in oC users may be due to an earlier diagnosis, biological effects of the oC or a combination of both.
• When acute or chronic disturbances of liver function occur the woman should be referred to a specialist for examination and advice.
• Epidemiological investigations have associated the use of combined oCs with an increased incidence of venous thromboembolism (VTE, deep venous thrombosis and pulmonary embolism). although the clinical relevance of this finding for etonogestrel (the biologically active metabolite of desogestrel) used as a contraceptive in the absence of an estrogenic component is unknown, the implant should be removed in the event of a confirmed thrombosis. Removal of the implant should also be considered in case of long-term immobilization due to surgery or illness. although IMPlanon nXT is a progestagen-only contraceptive, it is recommended to assess risk factors which are known to increase the risk of venous and arterial thromboembolism. Women with a history of thromboembolic disorders should be made aware of the possibility of a recurrence.
• There have been postmarketing reports of serious arterial and venous thromboembolic events, including cases of pulmonary emboli (some fatal), deep vein thrombosis, myocardial infarction, and strokes, in women using the non-radiopaque etonogestrel implant. IMPlanon nXT should be removed in the event of a thrombosis.
• If a sustained hypertension develops during the use of IMPlanon nXT, or if a significant increase in blood pressure does not adequately respond to antihypertensive therapy, IMPlanon nXT should be removed.
• Although progestagens may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using progestagen-only
contraceptives. However, diabetic women should be carefully observed while using progestagen-only contraceptives.
• Women who are being treated for hyperlipidemia should be followed closely if they elect to use IMPlanon nXT. Some progestagens may elevate lDl levels and may render the control of hyperlipidemia more difficult.
• 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 IMPlanon nXT. • The contraceptive effect of IMPlanon nXT is related
to the plasma levels of etonogestrel, which are inversely related to body weight, and decrease with time after insertion. The clinical experience in heavier women in the third year of use is limited. Therefore it cannot be excluded that the contraceptive effect in these women during the third year of use may be lower than for women of normal weight. HCPs may therefore consider earlier replacement of the implant in heavier women.
• Expulsion may occur especially if the implant is inserted not according to the instructions given in section 4.2.3 “How to insert IMPlanon nXT”, or as a consequence of a local inflammation.
• In rare cases, mostly related to either a too deep initial insertion (see also section 4.2.3 “How to insert IMPlanon nXT”) and/or to external forces (e.g.
manipulation of the implant or contact sports) the implant may migrate from the insertion site. In these cases localization of the implant may be more difficult and removal may require a larger incision (see also section 4.2.4 “How to remove IMPlanon nXT”). If the implant is not removed, contraception and the risk of progestagen-related undesirable effects may continue beyond the time desired by the woman.
• 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.
• The protection with traditional progestagen-only contraceptives against ectopic pregnancies is not as good as with combined oCs, which has been associated with the frequent occurrence of ovulations during the use of these methods. Despite the fact that IMPlanon
nXT will consistently inhibit ovulation, ectopic pregnancy should be taken into account in the differential diagnosis if the woman gets amenorrhea or abdominal pain.
• The following conditions have been reported both during pregnancy and during sex steroid use, but an association with the use of progestagens has not been established: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss and (hereditary) angioedema.
4.4.2
Medical examination/consultation
Prior to the initiation or reinstitution of IMPlanon nXT 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 (Section 4.3 “Contraindications”) and warnings (Section 4.4.1 “Warnings”). It is recommended that the woman returns for a medical check-up three months after insertion of IMPlanon nXT.
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 IMPlanon nXT does not protect against HIV (aIDS) and other sexually transmitted diseases.
4.4.3
Reduced efficacy
The efficacy of IMPlanon nXT may be reduced when concomitant medication is used (See section 4.5.1 “Interactions”).
4.4.4
Changes in the menstrual bleeding pattern
During the use of IMPlanon nXT, 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. Dysmenorrhea tended to improve while using IMPlanon nXT. The bleeding
pattern experienced during the first three months is broadly predictive of future bleeding patterns for many women. Information, counseling and the use of a bleeding diary can improve the woman’s acceptance of a bleeding pattern. Evaluation of vaginal bleeding should be done on an ad hoc basis and may include an examination to exclude gynaecological pathology or pregnancy.
Implanon nXT™: product monograph
part I: Health Care professional Information
4.5
Interaction with other medicinal products and other forms of
interaction
4.5.1
Interactions
• Influence of other medicinal products on IMPlanon nXT
Interactions between hormonal contraceptives and other medicinal products may lead to menstrual bleeding and / or contraceptive failure. no specific interaction studies have been performed with IMPlanon nXT. The following interactions have been reported in the literature (mainly with combined contraceptives but occasionally also with progestagen-only contraceptives).
Hepatic metabolism: Interactions can occur with medicinal
products that induce microsomal enzymes, specifically cytochrome P450 enzymes, which can result in increased clearance of sex hormones (e.g., phenytoin, phenobarbital, primidone, bosentan, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and the herbal remedy St. Johns wort). also HIV protease (e.g., ritonavir, nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine, efavirenz), and combinations of them, have been reported to potentially affect hepatic metabolism.
Women on treatment with any of the above mentioned drugs should use a non-hormonal contraceptive
method in addition to IMPlanon nXT. With microsomal enzyme-inducing drugs, the non-hormonal contraceptive method should be used during the time of concomitant drug administration and for 28 days after their
discontinuation.
In women on long-term treatment with hepatic enzyme-inducing drugs, it is recommended to remove the implant and to prescribe a non-hormonal method.
Increase in plasma hormone levels associated with co-administered drugs: Drugs (e.g., ketoconazole) that inhibit
microsomal enzymes, such as CYP3a4, may increase plasma hormone levels.
• Influence of IMPlanon nXT on other medicinal products Hormonal contraceptives may interfere with the
metabolism of other drugs. accordingly, plasma and tissue concentrations may either increase (e.g., ciclosporin) or decrease (e.g., lamotrigine).
note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
4.5.2
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 progestagen-only contraceptives is
not known.
4.6
Pregnancy and lactation
IMPlanon nXT is not indicated during pregnancy. If pregnancy occurs during use of IMPlanon nXT, the implant should be removed. animal studies have shown that very high doses of progestagenic substances may
cause masculinization of female fetuses. Extensive
epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used oCs prior to pregnancy, nor of a teratogenic effect when
-
4.6
4.5
oCs were inadvertently used during pregnancy. although this probably applies to all oCs, it is not clear whether this is also the case for IMPlanon nXT.
Pharmacovigilance data with various etonogestrel- and desogestrel-containing products (etonogestrel is a metabolite of desogestrel) do not indicate an increased risk.
Clinical data indicate that IMPlanon nXT does not influence the production or the quality (protein, lactose or fat concentrations) of breast milk. However, small amounts of etonogestrel are excreted in breast milk. Based on an average daily milk ingestion of 150 ml/kg, the mean daily infant etonogestrel dose calculated after one month of etonogestrel release is approximately 27 ng/kg/day. This corresponds to approximately 2.2% of the weight-adjusted
maternal daily dose and to approximately 0.2% of the estimated absolute maternal daily dose. Subsequently the milk etonogestrel concentration decreases with time during the lactation period.
long-term data are available on 38 children, whose mothers had an implant inserted during the 4th to 8th week postpartum. They were breast-fed for a mean duration of 14 months and followed-up to 36 months of age. Evaluation of growth, and physical and psychomotor development did not indicate any differences in comparison to nursing infants whose mothers used an IUD (n=33). nevertheless, development and growth of the child should be carefully followed. Based on the available data, IMPlanon nXT may be used during lactation and should be inserted after the 4th post partum week.
4.7
Effects on ability to drive and use machines
no observed effects
4.8
Undesirable effects
4.8.1
Serious undesirable effects
See Section 4.4.1 (“Warnings”)
4.8.2
other possible undesirable effects
During the use of IMPlanon nXT, 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 IMPlanon nXT. The bleeding pattern experienced during the first three months is broadly predictive of future bleeding patterns for many women.
Adverse reaction in MedDRA Term1
System Organ Class Very Common
> 1/10 < 1/10 ≥ 1/100Common <1/100 ≥ 1/1000Uncommon Infections and Infestations vaginal infection; Pharyngitis; rhinitis; urinary
tract infection;
Immune system disorders Hypersensitivity;
Metabolism and nutritional disorders
increased appetite; Psychiatric disorders affect lability; depressed
mood; nervousness; libido decreased;
anxiety; insomnia;
nervous system disorders Headache; Dizziness; Migraine; somnolence;
Vascular disorders hot flush;
Gastrointestinal disorders abdominal pain; nausea; flatulence
Vomiting; constipation; diarrhea
Skin and subcutaneous tissue disorders
acne alopecia hypertrichosis, rash;
pruritus Musculoskeletal and
connective tissue disorders
back pain; arthralgia; myalgia; musculoskeletal pain
Renal and urinary disorders Dysuria
Reproductive system and breast disorders
breast tenderness; breast pain; menstruation irregular Dysmenorrhea; ovarian cyst genital discharge; vulvovaginal discomfort; galactorrhea; breast enlargement; pruritus genital
General disorders and administration site condition
implant site pain; implant site reaction; fatigue; influenza like illness; pain
Pyrexia; edema
Investigations weight increased weight decreased
Implanon nXT™: product monograph
part I: Health Care professional Information
Possibly related undesirable effects reported in clinical trials have been listed in the Table below.
In a clinical trial of IMPlanon nXT, 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.
4.8.2
1 The most appropriate MedDRa term (version 10.1) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed,
During postmarketing surveillance, a clinically relevant rise in blood pressure has been observed in rare cases. Seborrhea 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 may be possible (see also section 4.4.1 “Warnings”). Surgical intervention might be necessary when removing the implant.
on rare occasions, ectopic pregnancies have been reported (see Section 4.4.1 “Warnings”).
In 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, some of which are discussed in more detail Section 4.4 “Special Warnings and Special Precautions for Use”.
4.9
overdose
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.
5
Pharmacological Properties
5.1
Pharmacodynamic properties
(Pharmacotherapeutic group: progestagens, aTC-classification G03AC08)
The IMPlanon nXT implant is a non-biodegradable, radiopaque, etonogestrel-containing implant for subdermal use, preloaded in a sterile, innovative, disposable
applicator. Etonogestrel is the biologically active metabolite of desogestrel, a progestagen widely used in 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. Clinical trials were conducted in women between 18 and 40 years. although no direct comparison was made, the
degree of protection against pregnancy is obtained, amongst other reasons, because the contraceptive action of IMPlanon nXT is not dependent on adherence to a daily, weekly, or monthly dosing regimen by the woman herself. The contraceptive action of etonogestrel is reversible, which is apparent from the rapid return of the normal menstrual cycle after removal of the implant. although etonogestrel inhibits ovulation, ovarian activity is not completely suppressed. Mean estradiol concentrations remain above the level seen in the early-follicular phase. In a two-year study, in which the bone mineral density in 44 users has been compared to that in a control group of 29 IUD-users no adverse effects on bone mass have been observed. no clinically relevant effects on lipid metabolism have been observed. The use of progestagen-containing contraceptives may have an effect on insulin resistance and glucose tolerance. Clinical trials further indicate that users of IMPlanon nXT often have a less painful menstrual
Implanon nXT™: product monograph
part I: Health Care professional Information
Implant insertion and removal characteristics In a clinical trial, IMPlanon nXT was inserted in 301 women. 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 seconds (standard deviation (SD) = 29.3, n=291). After insertion, 300 out of 301 (99.7%) IMPlanon nXT implants were palpable. The single, non-palpable implant was not inserted according to the instructions. For 293 of the 301 subjects, data on palpability was gathered before removal. The implant was palpable for all 293 subjects with data on palpability. For four subjects, palpability was not assessed and another four subjects were lost to follow-up before removal.
In two clinical trials with IMPlanon nXT implants, a total of 116 subjects underwent two-dimensional x-ray assessments at (after) insertion and/or (before) removal. For 101 out of 103 (98.1%) subjects for whom x-ray assessments were performed at insertion and before removal, IMPlanon nXT implants were clearly visible; for two subjects the implants were not clearly visible after insertion but were clearly visible before removal. The implants of the 13 subjects with x-ray assessment only at insertion (n=12) or only before removal (n=1) were all clearly visible.
5.2
Pharmacokinetic properties
absorption
after the insertion of the implant, etonogestrel is rapidly absorbed into the circulation. ovulation-inhibiting concentrations are reached within 1 day. Maximum serum concentrations (between 472 and 1270 pg/ml) are reached within 1 to 13 days. The release rate of the implant decreases with time. as a result, serum concentrations decline rapidly over the first few months. By the end of
the first year a mean concentration of approximately 200 pg/ml (range 150-261 pg/ml) is measured, which slowly decreases to 156 pg/ml (range 111-202 pg/ml) by the end of the third year. The variations observed in serum concentrations can be partly attributed to differences in body weight.
Distribution
Etonogestrel is for 95.5-99% bound to serum proteins, predominantly to albumin and to a lesser extent to sex hormone binding globulin. The central and total volume
of distribution are 27 l and 220 l, respectively, and hardly change during the use of IMPlanon nXT.
metabolism
Etonogestrel undergoes hydroxylation and reduction. Metabolites are conjugated to sulfates and glucuronides. animal studies show that enterohepatic circulation probably
does not contribute to the progestagenic activity of etonogestrel.
Elimination
after intravenous administration of etonogestrel, the mean elimination half-life is approximately 25 hours
and the serum clearance is approximately 7.5 l/hour. Both clearance and elimination-half-life remain constant during the treatment period. The excretion of etonogestrel and its metabolites, either as free steroids or as conjugates, is with urine and feces (ratio 1.5:1). after insertion in lactating women, etonogestrel is excreted in breast
milk with a milk/serum ratio of 0.44-0.50 during the first four months. In lactating women, the mean transfer of etonogestrel to the infant is approximately 0.2% of the estimated absolute maternal etonogestrel daily dose (2.2% when values are normalized per kg body weight). Concentrations show a gradual and statistically significant decrease over the time.
-
5.2
5.1
5.3
Preclinical safety data
Toxicological studies did not reveal any effects other than those, which can be explained on the basis of the hormonal
properties of etonogestrel, regardless of the route of administration.
6
Pharmaceutical Particulars
6.1
list of excipients
Implant
Core: Ethylene vinylacetate copolymer (28% vinyl acetate, 43 mg) barium sulfate (15 mg), magnesium stearate (0.1 mg).
Skin: Ethylene vinylacetate copolymer (15% vinyl acetate, 15 mg).
6.2
Incompatibilities
no incompatibilities are known
6.3
Shelf life
The shelf life of IMPlanon nXT is 5 years when stored as indicated under Section 6.4 “Special precautions for storage”.
IMPlanon nXT should not be inserted after the expiry date as indicated on the primary package.
6.4
Special precautions for storage
Store in the original package at 2° to 30°C.
6.5
nature and contents of container
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 a foil lidding. The blister pack is packed in a box together with the package leaflet.
6.6
Instructions for use and handling
Implanon nXT™: product monograph
part I: Health Care professional Information
7
Zinc Approval Number
WoMn-1025058-0064 May 2013
Merck Sharp & Dohme (I.a.) Corporation
a Philippine subsidiary of Merck & Co., Inc., Whitehouse Station, n.J., U.S.a. 26/F Philam Tower 8767 Paseo de Roxas, Makati City 1226
-
10
7
1
Table 1. Study Population1
IMPLANON IMPLANON NXT
All treated subjects 56 52
Subjects completing trial 32 32
Subjects who discontinued: 24 20
Due to AE/serious AE 17 15
Due to pregnancy 0 0
For other reason 7 5
Implanon nXT™: product monograph
part II: Select Clinical Trials
Select Clinical Trials
The following section summarizes 4 additional clinical trials that were not referred to in Part 1: investigating the bioequivalence and x-ray visibility of radiopaque (IMPLANON NXT™) and non-radiopaque (IMPLANON™)
etonogestrel implants (Schnabel et al, 2012)1; the tolerability
and clinical safety of IMPlanon (Blumenthal et al, 2008)2;
the impact of IMPlanon on menstrual bleeding
patterns (Mansour et al, 2008)3 and physician satisfaction; characteristics of a new applicator to insert
IMPLANON NXT; and the x-ray visibility of IMPLANON NXT
(Mansour et al, 2010).4
1
Bioequivalence of IMPLANON NXT and IMPLANON
1Bioequivalence and x-ray visibility of a radiopaque etonogestrel implant versus a non-radiopaque implant: a 3-year, randomized, double-blind study.
Schnabel P et al. Clin Drug Investig. 2012;32(6):413–422.
Objective: To determine whether IMPlanon nXT is bioequivalent in situ to IMPlanon, as well as to assess the x-ray visibility of IMPlanon nXT.
Design and Methods: IMPlanon nXT and IMPlanon were evaluated in a 3-year, randomized, double-blind, parallel-group study (n=108). Serum etonogestrel concentrations were measured throughout the study and bioequivalence determined based on peak concentration (Cmax) and area under the concentration-time curve at 6, 24, or 36 months (aUC6 mo, aUC24 mo, and aUC36 mo). Efficacy was measured by the occurrence of pregnancy, and safety by the occurrence of adverse events (aEs).
Results: a total of 32 women receiving either IMPlanon or IMPlanon nXT implants completed the 3-year study (Table 1).
Serum etonogestrel concentrations measured throughout the trial were similar for both IMPlanon and IMPlanon nXT groups (Figure 1). Key pharmacokinetic parameters, Cmax and aUC6 mo, aUC24 mo, and aUC36 mo, were also similar between the 2 groups, with 90% confidence intervals (CIs) for the ratios of the geometric means of these parameters for IMPLANON and IMPlanon nXT being within the predetermined range for bioequivalence (ie, 0.80–1.25) (Table 2). Thus, the implants are considered bioequivalent to each other.
Table 2. Results for Pharmacokinetic Parameters Evaluated to Determine the Bioequivalence of IMPlanon nXT
and IMPlanon1
IMPLANON NXT
geometric mean geometric meanIMPLANON Point Estimate Ratio of IMPLANON NXT/ IMPLANON Cmax (pg/ml) (n=50)1,083 (n=53)1,021 (95% CI: 0.89–1.27)1.06 aUC6 mo (pg•month/mL) (n=46)2,212 (n=46)2,210 (95% CI: 0.89–1.12)1.00 aUC24 mo (pg•month/mL) (n=37)5,783 (n=32)5,874 (95% CI: 0.87–1.12)0.98 aUC36 mo (pg•month/mL) (n=32)7,453 (n=30)7,487 (95% CI: 0.87–1.14)1.00
1,100 1,000 900 800 700 600 500 400 300 200 100 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Serum Etonogestr el, pg/mL
Months After Insertion
IMPLANON (n=53) IMPLANON NXT (n=50)
Figure 1. Serum Etonogestrel Concentrations Recorded in Subjects With IMPlanon (non-radiopaque) or IMPlanon nXT
(Radiopaque) Etonogestrel Implants1
Implants in subjects receiving IMPlanon were not visible with x-ray imaging either after insertion or before removal. In contrast, IMPLANON NXT was visible in 50 of 52 women (96.2%) after insertion and in all women before removal. In the 2 cases in which the implant was not visible after insertion, the x-ray imaging was determined to have been performed incorrectly
none of the women became pregnant after insertion or before removal of either IMPlanon or IMPlanon nXT. one woman in each group became pregnant within one month after implant removal, and both women discontinued
Table 3. Drug-related aEsa occurring in ≥5% of Women in Either Treatment Group1
Drug-related AEs Non-radiopaque ENG implant (n=56) Radiopaque ENG implant (n=52)
Total 49 (88%) 47 (90%) acne 15 (26.8) 11 (21.2) amenorrhoea 5 (8.9) 3 (5.8) Breast tenderness 1 (1.8) 4 (7.7) Breast pain 4 (7.1) 2 (3.8) Dysmenorrhoea 4 (7.1) 5 (9.6) Genital haemorrhage 23 (41.1) 24 (46.2) Headache 7 (12.5) 7 (13.5)
Implant site haematoma 16 (28.6) 16 (30.8)
Implant site pain 6 (10.7) 1 (1.9)
Metrorrhagia 8 (14.3) 9 (17.3) nausea 3 (5.4) 3 (5.8) oligomenorrhoea 3 (5.4) 0 (0.0) Pelvic pain 4 (7.1) 2 (3.8) Polymenorrhoea 0 (0.0) 3 (5.8) Vaginal discharge 1 (1.8) 3 (5.8) Viginal haemorrhage 18 (32.1) 21 (40.4) Vulvovaginal candidiasis 1 (1.8) 3 (5.8) Weight gain 5 (8.9) 4 (7.7)
abased on the Medical Directory for Regulatory Activities version 11.1. AEs=adverse events; ENG=etonogestrel.
Implanon nXT™: product monograph
part II: Select Clinical Trials
The incidence of drug-related adverse events (aEs) was similar between the 2 treatment groups (Table 3). Virtually all (106 of 108) women receiving an implant reported at least 1 aE during the study. The most common drug-related aEs in either implant group were genital haemorrhage, vaginal haemorrhage, and implant site haematoma (Table 3).
160 140 120 100 80 60 40 20 0 0 180 360 540 720 900 1080 1260 In vitr o r
elease of ENG, µg/day
Days
IMPLANON IMPLANON NXT
Figure 2. In Vitro Release Rate of Etonogestrel over 3 Years for IMPlanon and IMPlanon nXT (adapted from
Schnabel et al.)1
In vitro release rates of etonogestrel from the IMPlanon and IMPlanon nXT implants, as measured throughout the study, were essentially the same (Figure 2).
Conclusion: IMPlanon nXT is bioequivalent and exhibits similar total etonogestrel exposure and peak etonogestrel concentration as IMPlanon and is clearly visible with x-ray imaging. The efficacy and safety profiles of the 2 implants in this study were comparable.
2
Tolerability and Clinical Safety of IMPLANON™
2Tolerability and clinical safety of IMPlanon.
Blumenthal PD et al. Eur J Contracept Reprod Health Care. 2008;13(suppl 1):29–36.
Objective: To assess the tolerability and clinical safety profile of IMPlanon.
Design and Methods: Safety data for IMPlanon from 11 international clinical trials, including 10 completed phase 2 and phase 3 studies and one completed phase 4 study, were analyzed in 942 healthy, sexually active women of childbearing potential, 18 to 40 years of age with normal menstrual cycles (24 to 35 days). all placements of IMPlanon were conducted by trained physicians during an office visit between the first and fifth day of menstrual flow or 8 weeks after delivery in postpartum women. assessments included (1) aEs, defined as any new complaint/ symptom arising during treatment or any baseline complaint/symptom worsened in severity or frequency, (2) reasons for and rates of discontinuation, (3) insertion/removal complications, and (4) the condition of the implant site.
Table 4. all aEs and aEs Related to Study Drug2
All studies (N=942)
WHO preferred term All AEs n (%) Related AEs n (%)
Headache 233 (24.7) 144 (15.3) Vaginitis 136 (14.4) 13 (1.4) Weight increases 126 (13.4) 111 (11.8) acne 123 (13.1) 107 (11.4) Breast pain 121 (12.8) 96 (10.2) Upper respiratory Tract infection 119 (12.6) 0 (0) abdominal pain 103 (10.9) 49 (5.2) Pharyngitis 99 (10.5) 6 (0.6) leukorrhoea 90 (9.6) 10 (1.1) Influenza-like symptoms 72 (7.6) 18 (1.9) Dizziness 68 (7.2) 46 (4.9) Dysmenorrhoea 68 (7.2) 41 (4.4) Back pain 64 (6.8) 10 (1.1) Emotional lability 60 (6.4) 54 (5.7) nausea 58 (6.2) 24 (2.5) Pain 53 (5.6) 17 (1.8) Sinusitis 53 (5.6) 0 (0) nervousness 53 (5.6) 33 (3.5) Depression 52 (5.5) 33 (3.5)
Injection site pain 49 (5.2) 43 (4.6)
AEs=adverse events; WHO=World Health organization.
Implanon nXT™: product monograph
part II: Select Clinical Trials
Headache was the most commonly reported aE, affecting nearly a quarter of women, although it was judged by the investigators to be drug-related in only 15.3% of women (Table 4). The most common drug-related AEs included weight gain, acne, breast pain, emotional lability, and abdominal pain (Table 4). Fifty-six patients (of 942) reported a total of 77 serious AEs, the most common being gastrointestinal system disorders, which affected 10 patients (1.1%). Ten serious aEs were considered by the investigator to be possibly, probably, or definitely drug-related.
Table 5. Discontinuation Rate by Reason2
Primary reason for discontinuation IMPLANON (N=942) n (%)
adverse events 131 (13.9) Bleeding irregularities 98 (10.4) Planning pregnancy 39 (4.1) other reasons 33 (3.5) lost to follow-up 23 (2.4) amenorrhoea 7 (0.7)
A total of 308 participants (32.7%) discontinued use of IMPLANON prior to completing their respective trial, including 23 women who were lost to follow-up before IMPlanon removal (Table 5). adverse events and bleeding irregularities were the most common reasons for discontinuations (Table 5).
The rate of complications was low during both insertion (1.0%) and removal (1.7%), and insertion site pain at any time was reported in 3% of patients.
Conclusion: Multinational, clinical safety data integrated from 11 clinical trials demonstrated that treatment with IMPlanon over a total of 24,679 cycles of exposure was well-tolerated.
3
Impact of IMPLANON on Bleeding Patterns
3The effects of IMPlanon on menstrual bleeding patterns.
Mansour D et al. Eur J Contracept Reprod Health Care. 2008;13(suppl 1):13–28.
Objective: To analyze bleeding patterns associated with use of IMPlanon in 11 clinical trials conducted worldwide and to provide recommendations to physicians for optimized patient counseling.
Design and Methods: Bleeding patterns over 3 years from 11 clinical trials (n=923) with IMPlanon were analyzed using bleeding-spotting (B-S) records, changes in dysmenorrhoea from baseline, and discontinuation rates due to irregular bleeding. Reference period (RP) analysis was used to segment the bleeding information into 12 90-day periods. Bleeding patterns were classified as follows:
35 30 25 20 15 10 5 0 0-14 Days 15-28 Days 37.5 21.7 21.2 n=808 19.7 29-49 Days ≥50 Days Patients, %
Categories of Bleeding-Spotting Days 40
Figure 3. number of Bleeding-Spotting Days With IMPlanon in Reference Period 1.1 (90-Day Period, Days 29–118)3
Implanon nXT™: product monograph
part II: Select Clinical Trials
Clinically important bleeding patterns were based on the World Health organization (WHo)-recommended definitions: • Amenorrhea (no bleeding or spotting days during a 90-day reference period [RP])
• Infrequent bleeding (<3 bleeding-spotting [B-S] episodes during an RP, excluding amenorrhea) • Normal frequency (3–5 B-S episodes during an RP)
• Frequent bleeding (>5 B-S episodes during an RP)
• Prolonged bleeding (a B-S episode [uninterrupted] lasting >14 days during a 90-day RP)
Changes from baseline to end-of-study in dysmenorrhea by presence and severity (none, mild, severe, very severe) and patterns of discontinuation of IMPlanon were also analyzed.
Results: During days 29–118 after IMPlanon implantation (reference period RP 1.1), more subjects reported 0–14 B-S days than 15–28, 29–49, or ≥50 B-S days (Figure 3). The data shown are not statistically significant. Bleeding patterns were consistent during the subsequent follow-up (RP 2 – RP 12), with a mean number of B-S episodes of 2.4 per RP and a median number of B-S days ranging from 13 to 16 per RP.
The group of women with favourable bleeding patterns in the first RP tended to continue with this pattern throughout the first two years of use, whereas the group with unfavourable patterns had at least a 50% chance that the patterns would subsequently improve.
Table 6. Discontinuation Rates With IMPlanon Due to Bleeding Irregularity3
Bleeding Irregularity Discontinuation Rate (N=923), %
All irregularities 11.3
Frequent irregular bleeding 4.2
Prolonged menstrual flow 3.4
Spotting 1.4
Heavy menstrual flow 0.9
100 80 60 40 20 0
Resolved Decreased Severity 77
6 5.5 11.5
Developed or
Worsened No Change
Patients, %
Change in Dysmenorrhea From Baseline Women With Dysmenorrhea at Baseline (n=315)
Figure 4. Change in Dysmenorrhea From Baseline after up to 3 Years of Use of IMPlanon (adapted from Mansour et al.)3 Approximately one-half (48.7%) of women reported dysmenorrhea at baseline, and during the subsequent 3-year follow-up, dysmenorrhea resolved in most patients (Figure 4).
Across the studies, 11.3% of subjects discontinued IMPLANON because of bleeding irregularities, primarily frequent irregular bleeding and prolonged menstrual flow (Table 6).
Very satisfied Satisfied Not satisfied or dissatisfied Dissatisfied Very dissatisfied Overall Satisfaction Functionality Design and Technical Aspects Safety Used Time 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 Responses After
4 Insertions, % Responses After8 Insertions, % Responses After12 Insertions, % Figure 5. Frequency Distribution of Clinician Satisfaction Questionnaire Scoresa (n=23) (adapted from Mansour et al.)4
aEach domain consisted of one or more questions: overall satisfaction:1 question; functionality: 6 questions; design and technical aspects: 5 questions; safety: 3 questions; used time: 1 question.
Implanon nXT™: product monograph
part II: Select Clinical Trials
Conclusion: The bleeding pattern within the first 3 months of using IMPlanon was in many cases predictive of bleeding patterns observed over subsequent months. Favorable bleeding patterns tended to persist, while women with initially unfavorable bleeding patterns had at least a 50% chance of subsequent improvement. In most patients with dysmenorrhea at baseline who received IMPlanon, this symptom resolved over the 3 years of follow-up. Use of IMPLANON was associated with bleeding pattern irregularities that led to an 11.3% discontinuation rate over 3 years. Physicians administering IMPlanon should educate their patients about the expected changes in bleeding patterns, because such counseling may improve continuation rates.
4
Physician Satisfaction With IMPLANON
4Clinician satisfaction and insertion characteristics of a new applicator to insert radiopaque IMPlanon: an open-label noncontrolled, multicenter trial.
Mansour D et al. Contraception. 2010;82(3):243–249.
Objective: To evaluate the satisfaction of investigators performing IMPlanon insertions, and the insertion characteristics and x-ray visibility of IMPlanon nXT.
Design and Methods: Twenty-three experienced or inexperienced investigators performed insertions of IMPlanon nXT in 301 women after undergoing training for proper procedures with a next-generation applicator (NGA). After each insertion, characteristics including reported investigator experience, insertion time, implant site reactions, and x-ray detection of the radiopaque implant were recorded. Clinician satisfaction questionnaires following the 4th, 8th, and 12th insertions were also administered.
Results: after the first insertion the majority of investigators were satisfied/very satisfied with the applicator; by the 12th insertion, all investigators were satisfied or very satisfied overall, and nearly all were satisfied or very satisfied with functionality, design and technical aspects, safety, and time required for the insertion (Figure 5).
4
3
-Table 7. Insertion Time With IMPlanon nXT by all, Experienced, and Inexperienced Users4
Insertion Time (seconds)
Subjects (n) Mean (SD) Median Minimum Maximum
All users (23) 291 27.9 (29.3) 19.0 2 300 Inexperienced users (12) 150 36.6 (36.1) 25.0 7 300 Experienced users (11) 141 18.7 (15.1) 15 2 95 SD = standard deviation. Figure 6. X-ray visibility of radiopaque IMPlanon nXT implant4
all investigators were satisfied or very satisfied with the insertion time from the first insertion onwards, as well as with the retraction of the needle into the applicator after the insertion and with the color contrast between the obturator and implant. Ease of use, one-handed action, and fast insertion time were the most frequently reported advantages of the new applicator, with 98% of insertions considered easy.
Both experienced and inexperienced investigators performed the insertions rapidly, although the experienced investigators completed the insertions faster (Table 7).
no implant site reactions on the day of insertion were reported for 91.4% of the subjects; redness (4.0%), hematoma (3.3%), pain (1.0%), and swelling (0.7%) were reported in the remaining subjects.
Sixty-two subjects underwent 2 dimensional x-ray evaluations, and all implants were clearly visible on x-ray (Figure 6). In one case, the implant was not palpable after insertion but was clearly visible by x-ray. This single non-palpable implant was inserted by an inexperienced investigator who performed the insertion incorrectly, ie, in a standing position instead of sitting, and in a poorly illuminated room.
Conclusion: all investigators, regardless of insertion experience, were satisfied with IMPlanon nXT, which is designed for rapid, single-handed use. Difficulties with insertion were related to failure to
Implanon nXT™: product monograph
part II: Select Clinical Trials
References:
1. Schnabel P, Merki-Feld GS, Malvy A, et al. Bioequivalence and x-ray visibility of a radiopaque etonogestrel implant versus a non-radiopaque implant: a 3-year, randomized, double-blind study. Clin Drug Investig. 2012;32(6):413-422.
2. Blumenthal PD, Gemzell-Danielsson K, Marintcheva-Petrova M. Tolerability and clinical safety of Implanon.
Eur J Contracept Reprod Health Care. 2008;13 Suppl 1:29-36.
3. Mansour D, Korver T, Marintcheva-Petrova M, Fraser IS. The effects of Implanon on menstrual bleeding patterns.
Eur J Contracept Reprod Health Care. 2008;13 Suppl 1:13-28.
4. Mansour D, Mommers E, Teede H, et al. Clinician satisfaction and insertion characteristics of a new applicator to insert radiopaque Implanon: an open-label, noncontrolled, multicenter trial. Contraception. 2010;82(3):243-249.
Implanon nXT™: product monograph
part III: Consumer Information
In this leaflet:
1. What Is IMPLANON NXT and What Is It Used for?
34
2. What Do You Have to Know Before IMPLANON NXT Is Inserted?
34-37
3. How to Use IMPLANON NXT
38
4. Possible Side Effects
39
5. How to Store IMPLANON NXT
40
6. Further Information
40-43
7. Information for the Health Care Professional
45-50
The name of your contraceptive implant is: Implanon nXT, implant for subdermal use Composition in full
• The active substance is: Etonogestrel (68 mg) • The other ingredients are:
ethylene vinyl acetate copolymer barium sulfate
magnesium stearate
The following company is responsible for marketing IMPlanon nXT: Merck Sharp & Dohme (I.A.) Corporation
a Philippine subsidiary of Merck & Co., Inc., Whitehouse Station, n.J., U.S.a. 26/F Philam Tower 8767 Paseo de Roxas, Makati City 1226
Manufacturer: IMPlanon nXT is produced by Merck Sharp & Dohme (I.A.) Corporation
a Philippine subsidiary of Merck & Co., Inc., Whitehouse Station, n.J., U.S.a. IMPlanon nXT, 68 mg implant for subdermal use
Etonogestrel
Read all of this leaflet carefully before you start using this medicine.
• The presented information may help you to decide to use IMPLANON NXT and to
use it properly and safely.
• Keep this leaflet. You may need to read it again during the use of IMPLANON NXT,
since it is important to remain aware of potential future issues.
• This medicine has been prescribed for you. Do not pass it on to others. It may harm
them, even if their symptoms are the same as yours.
• If you have any further questions, ask your doctor or pharmacist.
• If any of the side effects gets serious, or if you notice any side effects not listed in
this leaflet, please tell your doctor or pharmacist.
1
What Is IMPLANON NXT and What Is It Used for?
IMPlanon nXT is a contraceptive implant preloaded in a disposable applicator. The implant is a small, soft, flexible, plastic rod, 4 cm in length and 2 mm in diameter which contains 68 milligrams of the active substance, etonogestrel. The applicator allows the healthcare
professional to insert the implant just under the skin of your upper arm. Etonogestrel is a synthetic female hormone
resembling progesterone. a small amount of etonogestrel is continuously released into the bloodstream. The implant itself is made of ethylene vinyl acetate copolymer, a plastic that will not dissolve in the body. It also contains a small amount of barium sulfate (which renders it visible under X-ray), and magnesium stearate.
Implanon nXT is used to prevent pregnancy. How does Implanon nXT work?
The implant is inserted just below the skin. The active compound, etonogestrel, works in two ways:
• It prevents the release of an egg cell from the ovaries. • It causes changes in the cervix that make it difficult for
sperm to enter the womb.
as a result, IMPlanon nXT protects you against pregnancy for a period of three years, but if you are overweight the doctor may advise you to replace the implant earlier. IMPlanon nXT is one of several means of preventing pregnancy. another frequently used birth control method is the combined Pill. In contrast to combined Pills, IMPlanon nXT can be used by women
who may not, or do not want to use estrogens. When you use IMPlanon nXT you do not have to remember to take a pill every day. This is one of the reasons that IMPlanon nXT is very reliable (over 99% effective). If in rare cases the implant is not inserted correctly or is not inserted at all, you may not be protected against pregnancy. When you are using IMPlanon nXT, your menstrual bleeding may change and become absent, irregular, infrequent, frequent, prolonged, or rarely heavy. The bleeding pattern that you experience during the first three months generally indicates your future bleeding pattern. Painful periods may improve. You may stop using IMPlanon nXT at any time (See also
‘When you want to stop using IMPLANON NXT’).
2
What Do You Have to Know Before IMPLANON NXT
Is Inserted?
Hormonal contraceptives, also including Implanon nXT, do not protect against HIV infection (aIDS) or any other sexually transmitted disease.
Do not use Implanon nXT
Do not use IMPlanon nXT if you have any of the conditions listed below. If any of these conditions apply to you, tell your doctor before IMPlanon nXT is inserted. Your doctor may advise you to use a non-hormonal method of birth control.
• if you are allergic to etonogestrel or any of the other ingredients of IMPlanon nXT.
• if you have or have had jaundice (yellowing of the skin) or severe liver disease (when the liver is not functioning properly), or a liver tumour.
• if you have (had) or if you may have cancer of the breast or of the genital organs.
• if you have any unexplained vaginal bleeding. • if you are pregnant or think you might be pregnant.