Implanon Workshop'13

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Clinical Information and

Practical Workshop DR NORAZIANA ABD WAHAO&G DEPARTMENTIIUM4TH JULY 2013


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IMPLANON NXT

Subdermal, long-acting hormonal contraceptive,effective for up to 3 years1

Progestogen-only implant preloaded in adisposable applicator1

IMPLANON NXT is radiopaque1 and bioequivalentto IMPLANON2

IMPLANONNXT studied in an open label study in 6countries (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


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IMPLANON


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Implant

Skin, rate-controlling membrane: (0.06 mm)

(14% vinyl acetate) EVA

4 cm

Core: ethylene vinyl acetate (EVA) copolymer (28% vinyl acetate)

etonogestrel (68 mg) barium sulfate

2 mm

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

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


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Applicator

Preloaded, sterile and disposableapplicator1

Designed to facilitate subdermalinsertion of the implant2

To be used only in accordance withinstructions for insertion, removal andreplacement, and by HCPs familiar withthe insertion procedure

HCPs familiar with the previousapplicator need to familiarisethemselves with IMPLANONNXT1.IMPLANON NXT Local Approved Product Information RA 0450 OS S9 (ref . 9.0)

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


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Clinical Data


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Efficacy

When inserted correctly, IMPLANON is over 99% effective

1

Majority of reported pregnancies in clinical practice related to insertionissues (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 thanfor 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)


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Quickly Reversile

Data on file, MSD

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


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Bone Mineral Density

Although IMPLANON inhibits ovulation, ovarian activity is notcompletely suppressed. Mean estradiol concentrations remainabove the level seen in the early-follicular phase.

In a two-year study, in which the bone mineral density in 44IMPLANON users has been compared with that in a controlgroup of 29 IUD-users no adverse effects on bone mass havebeen observed.

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


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Estradiol level during treatment

Last

measurement

1250

1000

750

500

250

0Baseline Month 12* Month 24**

1500

Mean

estradiol(pmol/L)

IMPLANON (n = 44)

Copper IUD (n = 29)

Despite ovulation inhibition mean estradiol concentrations were notsignificantly different between the two treatment groups.

Beerthuizen R et al. Human Reproduction 15(1) (2000) 118-122.

Adapted from Beerthuizen et al

*38 Implanon users, 26 IUD users

** 35 Implanon users, 28 IUD users

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

medicated IUD


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A t f bl di tt i


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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 bloodthat required at most one sanitary towel or tampon per day.

Bleeding-free day: a day during which neither bleeding norspotting was entered in the diary.

B-S episodes: one or more consecutive days during whichbleeding 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 forCounselling

A womans menstrual pattern might change and beless 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 naturalmenstrual cycles.- comparable to number of days on combined oral

contraceptive (COC)

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

Bl di P tt E i d D i


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Bleeding Patterns Experienced During

IMPLANON Use


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

Pecentage bleeding Incidences ove rReference Period

0

1020

30

40

50

60

1.1 2 3 4 5 6 7 8 9 10 11 12

Reference Period (each interval represents 90 days)

Bleeding

Incidences(%)

Amenor rhea

Infrequent

Normal*

Frequent

Prolonged

Amenorrhoea: no bleeding or

spotting days throughout the90 day reference period (RP)

Infrequent bleeding: less than3 B/S episodes in a 90 day RP,excluding amenorrhoea

Normal frequency: 35 B/Sepisodes in a 90 day RP

Frequent bleeding: more

than 5 B/S episodes in a 90day RP

Prolonged bleeding: any B/Sepisode (uninterrupted)lasting more than 14 days in a90 day RP

Adapted from Mansour et al


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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.



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Adverse Eventsthought to be related to IMPLANON in >5% of women

WHO preferred term *Related AE % Discontinuation %(due to AE)

Headache 15.3 1.6

Weight increase 11.8 2.3

Acne 11.4 1.3

Breast pain 10.2 < 1

Emotional lability 5.7 2.3

Abdominal pain 5.2 < 1

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

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

Adapted from Blumenthal et al

W i ht I f B li t L t


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Weight Increase from Baseline to Last

Measurement

Weight increase in kg

n=942

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

31

25 24

911

0

5

10

15

20

25

30

35

40

0/ loss 0.1- 2.5 2.6-5 5.1-7.5 >7.5

% of women

Adapted from Blumenthal et al.


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Use While Breastfeeding

Small amounts of etonogestrel are excreted in breast milk (~ 0.2% ofestimated 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 headcircumference

IMPLANON NXT may be used during lactation and should be inserted

after 4th post-partum week.


Reinprayoon D. Contraception (2000) 239-246

For further information about breast feeding, refer to the approved product information.


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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 theexcipients of IMPLANON NXT

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

Drug Interactions


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Drug Interactions

Interactions can occur with medicinal products that induce microsomalenzymes, specifically cytochrome P450 enzymes, which can result inincreased 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), andcombinations of them, have been reported to potentially affect

hepatic metabolism

Drug Interactions


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Women on concomitant treatment with any of the drugsmentioned,

- To use non-hormonal contraceptive methods inaddition to IMPLANON NXT

- With microsomal enzyme-inducing drugs, the non-hormonalcontraceptive method should be used during the time of concomitantdrug administration and for 28 days after discontinuation.

Women on long-term treatment with hepatic enzyme-inducing drugs,

- Remove IMPLANON NXT

- To use a non-hormonal method.

Drug Interactions



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IMPLANON NXT Summary

Subdermal long-acting hormonalcontraceptive

Radiopaque

When inserted correctly, IMPLANON NXT is more

than 99% effective

Should be removed after 3 years

Rapid onset of action

Quickly reversible



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IMPLANON NXT Summary (continued)

Most common side effect associated withdiscontinuation is irregular and unpredictablebleeding

Counselling of women is very important



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Counselling


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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

Contraindications

Side effects, emphasising thealteration of the menstrual bleeding

pattern No protection against STD or HIV

Alterations in

bleeding pattern: During the use of IMPLANON NXT,

women are likely to have changes intheir menstrual bleeding pattern.

A significant proportion of women willhave relatively little bleeding

Some women will experience irregularbleeding. Some will experience

frequent and/or prolonged bleeding

The bleeding pattern experienced

during the first three months is broadlypredictive of future bleeding patterns

Dysmenorrhoea may improve

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

Recommended


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Recommended

Timing of Insertion

Previous method Timing of insertion

None Day 1-5 of cycle

Combined method (COC - Combined Oral

Contraceptive, patch, ring)During hormone-free week

POPProgestogen Only PillInsert the implant on the day after

stopping the POP

IMPLANON/IUS Same day as removal

Injectable Progestogen Only When next injection is due

First trimester Termination of Pregnancy Same day

Second trimester Termination of

Pregnancy/deliveryDay 21-28 following termination


i i i id


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Insertion Animation Video


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Live Insertion Video

If you cannot feel the implant or


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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 thelocal supplier for instructions

Please be aware that implants inserted prior to the launch ofIMPLANON NXT are not radiopaque and will only be visible underUSS or MRI.


If you cannot feel the implant or in


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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 toverify the presence of the implant by measuring theetonogestrel level in a blood sample of the subject. Inthis case the local supplier will provide the appropriateprocedure

Until you have verified the presence of the implant, anon-hormonal contraceptive method must be used



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Localisation before Removal

L li ti


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Localisation

Localisation is an essential component of the insertion andremoval 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 untilthe presence of the implant can be verified.


Localisation Before Removal


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Exploratory surgery without knowledge of the exactlocation of the implant is strongly discouraged

Removal of deeply inserted implants should beconducted with caution in order to prevent damage to

deeper neural or vascular structures in the arm and

should be performed by healthcare providers familiarwith the anatomy of the arm




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Two different implants possibly presented forremoval:

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

Detecting and Imaging of IMPLANON


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and IMPLANON NXT

IMPLANONnon-radiopaque

IMPLANON NXTradiopaque

Visible on X ray no yes

Visible on US yes yes

Visible on CT no yes

Visible on MRI yes yes

Positive ENG Assay yes yes

If the imaging results are inconclusive, the presence of IMPLANON NXT can be verified

by ENG determination.


Radiopaque Implant


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p q pLocalisation X-ray

Ultrasound Localisation


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Ultrasound Localisation

Ultrasound

Should be performed by a HealthCare Provider with proper equipment andwho 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 imageenhancing software

With correct technique and transducer, most implants can be located

Perform removal shortly after/during localisation to increase accuracy oflocation

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

1. Lantz A, Nosher JL, Pasquale S, Siegel RL, Contraception 1997:56:323-3272. JamesP, Trenary J, Australian and New Zealand Journal of Obstetrics and Gynaecology 2006;46:225-228

Properly Inserted IMPLANON


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Transverse Image

acoustic shadow

implant

MRI Localisation


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MRI Localisation

MRI Radiopaque implant appears as a

hypointense area

Gadolinium administered to differentiate theimplant and vessels; vessels will appearhyperintense, implant appears hypointense

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

MRIIMPLANON appears as a hypointense area:

Important to differentiate from blood vessels


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MRI Important to differentiate from blood vessels Can be followed through images for 40 mm

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

Deep Placement Into Biceps Muscle


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Deep Placement Into Biceps Muscle

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

ENG Assay


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ENG Assay

Serum etonogestrel levels

Can indicate presence, but not confirm location

Obtain when unable to localise by palpation and imagingtechniques

The woman should not be using other contraceptive

hormones (cross reactivity)


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Removal: Steps and Techniques

Removal


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Removal

Indications forremoval

Womans request

Medical conditions

At the end of 3 yearsof use

Should be performed only byHealthCare Providers familiarwith the procedure

Prior to removal carefully readthe full Product Information

If the woman does not wish tobecome pregnant, anothercontraceptive method should be

started immediately (return topre-existing fertility may be very

rapid)

Removal


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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 experiencedcolleague

If implant cannot be removed, please contact local supplier for furtherguidance


Removal Animation Video


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Removal Animation Video


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Questions


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How to replace

IMPLANON NXT

How to Replace IMPLANON NXT


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Replacement of IMPLANON NXT should only be performed under

aseptic conditions and only by a healthcare provider who is familiarwith the removal and insertion procedure

Immediate replacement can be done after removal of the previousimplant 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 ofcontraception is necessary




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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 justunder the skin commencing at the removal incision along the insertioncanal

Inserting the needle to its full length is crucial; failure to do so will resultin a partly visible implant in the removal incision in the skin

If partial extrusion occurs, discard the implant and reinsert new sterileimplant

Always verify the presence of the rod by palpation. Request that the

woman palpate the rod as well.




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After replacing the implant, close the incision with a steri-

strip and apply an adhesive bandage

Apply sterile gauze with a pressure bandage to minimise

bruising. The woman may remove the pressure bandageafter 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 thewoman's medical record.

The old implant and the applicator must be disposed of by

the removing physician in accordance with local

legislation.



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Questions


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Thank you

Documents

Implanon Workshop'13