Clinical Information and Practical Workshop

DR NORAZIANA ABD WAHAB O&G DEPARTMENT IIUM 4TH JULY 2013

Agenda
Clinical Information Counselling Insertion Procedure and practise Localisation Removal Procedure and practise Reinsertion Conclusion

IMPLANON NXT

Subdermal, long-acting hormonal contraceptive, effective for up to 3 years1 Progestogen-only implant preloaded in a disposable applicator1 IMPLANON NXT is radiopaque1 and bioequivalent to IMPLANON2 IMPLANON NXT studied in an open label study in 6 countries (clinician satisfaction and insertion) 3

1. IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0) 2. Data on file, MSD

3. Mansour et.al. Contraception 82 (2010) 243-249

IMPLANON

Implant
4 cm

2 mm

Core:

ethylene vinyl acetate (EVA) copolymer (28% vinyl acetate) etonogestrel (68 mg) barium sulfate

Skin, rate-controlling membrane: (0.06 mm) (14% vinyl acetate) EVA

Release Rate: Initial- 60 g/day Week 5 to 6 60 to 70 g/day End of 1st year 35 to 45 g/day End of 2nd year 30 to 40 g/day End of 3rd year 25 to 30 g/day

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

Applicator

Preloaded, sterile and disposable applicator1 Designed to facilitate subdermal insertion of the implant2 To be used only in accordance with instructions for insertion, removal and replacement, and by HCPs familiar with the insertion procedure HCPs familiar with the previous applicator need to familiarise themselves with IMPLANON NXT

1.IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref. 9.0) 2. Mansour et al. Contraception 82(2010) 243-249

Clinical Data

Efficacy

When inserted correctly, IMPLANON is over 99% effective1 Majority of reported pregnancies in clinical practice related to insertion issues (incorrect timing, non-insertion, etc.) 1 No method of contraception is 100% effective Some medicines which reduce the efficacy of oral contraceptives may reduce the efficacy of IMPLANON NXT as well The clinical experience in heavier women in the 3rd year of use is limited. the contraceptive effect during the 3rd year of use may be lower than for women of normal weight. HCPs can consider earlier replacement of the implant in heavier women.

1. Graesslin et al, European Journal of Contraception and Reproductive Health Care,13:1,4-12 2008

2.IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref. 9.0)

Main Mechanisms of Action

Ovulation inhibition
In clinical trials, ovulations were not observed in the first two years of use and only rarely in the third year

Increased viscosity of cervical mucus

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

Quickly Reversile
In 2 separate clinical studies, etonogestrel levels of women with IMPLANON were measured at fixed intervals

ENG release rate: 60-70 g/day, decreasing to 25-30 g/day after 3 years

Data on file, MSD

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Bone Mineral Density

Although IMPLANON 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 IMPLANON users has been compared with that in a control group of 29 IUD-users no adverse effects on bone mass have been observed.

1.IMPLANION NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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Estradiol level during treatment

In a 2-years prospective,comparative study of IMPLANON and a non-hormonal medicated IUD
1500

Mean estradiol (pmol/L)

1250 1000 750 500

IMPLANON (n = 44) Copper IUD (n = 29)

*38 Implanon users, 26 IUD users ** 35 Implanon users, 28 IUD users

250
0 Baseline Month 12* Month 24** Last measurement

Adapted from Beerthuizen et al

Despite ovulation inhibition mean estradiol concentrations were not significantly different between the two treatment groups.
Beerthuizen R et al. Human Reproduction 15(1) (2000) 118-122.

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Bleeding Patterns

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 Bleeding pattern experienced during the first three months is broadly predictive of future bleeding patterns for many women. Amenorrhea was reported in about 1 of 5 women while another 1 of 5 women reported frequent and/or prolonged bleeding Information, counselling and the use of a bleeding diary can improve the womans acceptance of a bleeding pattern. Evaluation of vaginal bleeding should be done on an ad hoc basis to exclude gynaecological pathology or pregnancy

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IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref. 9.0)

Assessment of bleeding patterns in the study

Bleeding day: any day with vaginal discharge containing blood that required more than one sanitary towel or tampon per day.

Spotting day: any day with vaginal discharge containing blood that required at most one sanitary towel or tampon per day.
Bleeding-free day: a day during which neither bleeding nor spotting was entered in the diary. B-S episodes: one or more consecutive days during which bleeding or spotting was entered in the diary, bounded by bleeding-free days.

Mansour et al European Journal of Contraception and Reproductive Health 2008 (13-28)

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IMPLANON Bleeding In Perspective for Counselling

A womans menstrual pattern might change and be less predictable when using IMPLANON, also occurs in other Progestogen-only contraceptives In general, mean numbers of B-S days and bleeding episodes are fewer than number reported in natural menstrual cycles. - comparable to number of days on combined oral contraceptive (COC)

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Mansour et al, European Journal of Contraception and Reproductive Health Care (2008) 13-28

Bleeding Patterns Experienced During IMPLANON Use

Bleeding Incidences (%)

Amenorrhoea: no bleeding or spotting days throughout the 90 day reference period (RP) Infrequent bleeding: less than 3 B/S episodes in a 90 day RP, excluding amenorrhoea Normal frequency: 3 5 B/S episodes in a 90 day RP Frequent bleeding: more than 5 B/S episodes in a 90 day RP Prolonged bleeding: any B/S episode (uninterrupted) lasting more than 14 days in a 90 day RP

Pecentage bleeding Incidences over Reference Period

60 50 40 30 20 10 0 1.1 2 3 4 5 6 7 8 9 10 11 12
Reference Period (each interval represents 90 days)
Amenorrhea Inf requent Normal* Frequent Prolonged

Adapted from Mansour et al

* Normal refers to normal frequency (ie 3-5 bleeding episodes in a 90 day reference period), including prolonged episodes (>14 days) 16

Mansour et al, European Journal of Contraception and Reproductive Health Care (2008) 13-28

Dysmenorrhoea
In an analysis of 11 clinical trials (n=923),

At baseline, 48.7% of subject reported dymenorrhoea. During the use of IMPLANON, 77% reported that their symptoms resolved, and 6% reported decreased severity. Dysmenorrhoea developed or became worse in 5.5% of women.

Mansour et al, European Journal of Contraception and Reproductive Health Care (2008) 13-28

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Adverse Events
thought to be related to IMPLANON in >5% of women
WHO preferred term
Headache Weight increase Acne Breast pain Emotional lability Abdominal pain
Adapted from Blumenthal et al

*Related AE %
15.3 11.8 11.4 10.2 5.7 5.2

Discontinuation % (due to AE)

1.6 2.3 1.3 <1 2.3 <1

*Related AE is defined as possibly, probably, or definitely related to study drug according to the investigator.

Blumenthal et al, European Journal of Contraception and Reproductive Health Care (2008) 29-36

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Weight Increase from Baseline to Last Measurement

40 35 30 25 20 15 10 5 0 0/ loss 0.1- 2.5 2.6-5 5.1-7.5 >7.5

n=942
31
25 24 % of women

11

Weight increase in kg
Adapted from Blumenthal et al.

Blumenthal et al, European Journal of Contraception and Reproductive Health Care (2008) 29-36

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Use While Breastfeeding

Small amounts of etonogestrel are excreted in breast milk (~ 0.2% of estimated absolute maternal daily dose) In a comparative study of breastfeeding women (Cu-IUD (n=38) vs. IMPLANON (n=42)) and infants followed up to 36 months:
- No significant difference in composition of breast milk when measured at regular intervals. - No significant difference for body length, body weight and biparietal head circumference

IMPLANON NXT may be used during lactation and should be inserted after 4th post-partum week.
For further information about breast feeding, refer to the approved product information.

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0) Reinprayoon D. Contraception (2000) 239-246

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Contraindications

Known or suspected pregnancy Active venous thromboembolic disorder Known or suspected sex steroid sensitive malignancies 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

IMPLANON NXTTM Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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Drug Interactions
Interactions can occur with medicinal products that induce microsomal enzymes, specifically cytochrome P450 enzymes, which can result in increased clearance of sex hormones, such as:

phenytoin barbiturates primidone 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), and combinations of them, have been reported to potentially affect hepatic metabolism
IMPLANON NXTTM Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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Drug Interactions
Women

on concomitant treatment with any of the drugs mentioned, - To use non-hormonal contraceptive methods 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 discontinuation.
Women

on long-term treatment with hepatic enzymeinducing drugs, - Remove IMPLANON NXT

- To use a non-hormonal method.

IMPLANON NXTTM Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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IMPLANON NXT Summary

Subdermal long-acting hormonal contraceptive Radiopaque When inserted correctly, IMPLANON NXT is more than 99% effective Should be removed after 3 years Rapid onset of action Quickly reversible

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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IMPLANON NXT Summary (continued)

Most common side effect associated with discontinuation is irregular and unpredictable bleeding Counselling of women is very important

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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Counselling

Key Counselling Points

Discuss benefits, risks, and possible side effects:
Highly effective for up to 3 years No method of contraception is 100% effective Return to fertility If inserted correctly, can be easily removed any time Should not be used for longer than 3 years

Alterations in bleeding pattern:

During the use of IMPLANON NXT, women are likely to have changes in their menstrual bleeding pattern. A significant proportion of women will have relatively little bleeding Some women will experience irregular bleeding. Some will experience frequent and/or prolonged bleeding The bleeding pattern experienced during the first three months is broadly predictive of future bleeding patterns Dysmenorrhoea may improve

Contraindications
Side effects, emphasising the alteration of the menstrual bleeding pattern No protection against STD or HIV

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

Mansour et al, European Journal of Contraception and Reproductive Health Care (2008) 13-28

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Recommended Timing of Insertion

Previous method
None Combined method (COC - Combined Oral Contraceptive, patch, ring) POP Progestogen Only Pill IMPLANON/IUS Injectable Progestogen Only First trimester Termination of Pregnancy Second trimester Termination of Pregnancy/delivery

Timing of insertion
Day 1-5 of cycle

During hormone-free week

Insert the implant on the day after stopping the POP Same day as removal When next injection is due Same day Day 21-28 following termination

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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Insertion Animation Video

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Live Insertion Video

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If you cannot feel the implant or doubt its presence

Check the applicator. The needle should be fully retracted and only the purple tip of the obturator should be visible The following imaging methods can be used to confirm the presence of IMPLANON NXT: Two-dimensional x-ray (x-ray) X-ray computerised tomography (CT) Ultrasound scanning (USS) with high frequency linear array transducer (10MHz or greater) Magnetic resonance imaging (MRI) Prior to the application of any of these methods for the localisation of an implant it is recommended to consult the local supplier for instructions Please be aware that implants inserted prior to the launch of IMPLANON NXT are not radiopaque and will only be visible under USS or MRI.
IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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If you cannot feel the implant or in doubt of its presence

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

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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Localisation before Removal

Localisation

Localisation is an essential component of the insertion and removal process Always localise:
immediately after insertion immediately prior to removal

Localisation begins with palpation If the implant is not palpable after insertion, confirm its presence in the arm with imaging techniques (ultrasound, X-ray, CT scan, MRI) as soon as possible A non-hormonal contraceptive method must be used until the presence of the implant can be verified.
IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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Localisation Before Removal

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 healthcare providers familiar with the anatomy of the arm

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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Localisation Before Removal

Two different implants possibly presented for removal:

Non-radiopaque IMPLANON
Generally inserted before launch of IMPLANON NXT Previous version User Card

Radiopaque IMPLANON NXT

Inserted after launch of IMPLANON NXT New version User Card

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Detecting and Imaging of IMPLANON and IMPLANON NXT

IMPLANON non-radiopaque Visible on X ray Visible on US Visible on CT no yes no IMPLANON NXT radiopaque yes yes yes

Visible on MRI
Positive ENG Assay

yes
yes

yes
yes

If the imaging results are inconclusive, the presence of IMPLANON NXT can be verified by ENG determination.

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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Radiopaque Implant
Localisation X-ray

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Ultrasound Localisation

Ultrasound
Should be performed by a HealthCare Provider with proper equipment and who is familiar with implant localisation procedures
Ultrasound scanning (USS) with high frequency linear array transducer ( 10MHz)

Set US focus superficial (increases visibility of shadow) and switch off image enhancing software With correct technique and transducer, most implants can be located Perform removal shortly after/during localisation to increase accuracy of location

Ultrasound characteristics
Sharp acoustic shadow below the implant in the transverse position Implant is a small echogenic spot (2 mm) when viewed in transverse position

2.

1. Lantz A, Nosher JL, Pasquale S, Siegel RL, Contraception 1997:56:323-327 JamesP, Trenary J, Australian and New Zealand Journal of Obstetrics and Gynaecology 2006;46:225-228

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Properly Inserted IMPLANON Transverse Image

implant

acoustic shadow

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MRI Localisation
MRI

Radiopaque implant appears as a hypointense area

Gadolinium administered to differentiate the implant and vessels; vessels will appear hyperintense, implant appears hypointense

1.Merki-Feld,GS, Brekenfeld, C,Mihhe,B,Keller,PJ,Contraception 63(2001) 325-328

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MRI

IMPLANON appears as a hypointense area: Important to differentiate from blood vessels

Can be followed through images for 40 mm

Shulman L.,Gabriel H.. Contraception 73 (2006), 325-330

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Deep Placement Into Biceps Muscle

Shulman L.,Gabriel H.. Contraception 73 (2006), 325-330

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ENG Assay
Serum etonogestrel levels

Can indicate presence, but not confirm location Obtain when unable to localise by palpation and imaging techniques The woman should not be using other contraceptive hormones (cross reactivity)

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Removal: Steps and Techniques

Removal

Indications for removal

Womans request Medical conditions At the end of 3 years of use

Should be performed only by HealthCare Providers familiar with the procedure Prior to removal carefully read the full Product Information If the woman does not wish to become pregnant, another contraceptive method should be started immediately (return to pre-existing fertility may be very rapid)
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Removal

Possible situations complicating localisation and/or removal:

Formation of fibrosis Implant not palpable Implant not present Slight migration Difficult removal due to deep insertion

Only start removal procedure if location of implant is confirmed In case of broken or damaged implant, remove and contact local supplier In case of a difficult removal, consider referral to an experienced colleague If implant cannot be removed, please contact local supplier for further guidance

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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Removal Animation Video

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Questions

How to replace IMPLANON NXT

How to Replace IMPLANON NXT

Replacement of IMPLANON NXT should only be performed under aseptic conditions and only by a healthcare provider who is familiar with the removal and insertion procedure Immediate replacement can be done after removal of the previous implant as described in How to remove IMPLANON NXT The procedure to replace IMPLANON NXT is similar to the insertion procedure 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 implant is replaced immediately, no backup method of contraception is necessary

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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How to Replace IMPLANON NXT

If the same incision is being used, the instructions below must also be taken into account The small incision made during the removal procedure can be used as the entrance for the needle of the new applicator Anaesthetise the insertion site with 2 ml lidocaine (1%) applied just under the skin commencing at the removal incision along the insertion canal Inserting the needle to its full length is crucial; failure to do so will result in a partly visible implant in the removal incision in the skin If partial extrusion occurs, discard the implant and reinsert new sterile implant Always verify the presence of the rod by palpation. Request that the woman palpate the rod as well.

IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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How to Replace IMPLANON NXT

After replacing the implant, close the incision with a steristrip and apply an adhesive bandage Apply sterile gauze with a pressure bandage to minimise bruising. The woman may remove the pressure bandage after 24 hours and the small bandage 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 old implant and the applicator must be disposed of by the removing physician in accordance with local legislation.
IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref.9.0)

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Questions

Thank you