Jad e lle ® Le vo n o rge stre l Ro d Im p lan ts:

A Su m m ary o f Scie n tific D ata

an d Le sso n s Le arn e d fro m
Pro gram m atic Ex p e rie n ce

Irvin g Sivin , Harold Nash , an d San d ra Wald m an

P O P U L A T I O N C O U N C I L N E W Y O R K
 Jad e lle ® Le vo n o rge stre l Ro d Im p lan ts:
A Su m m ary o f Scie n tific D ata
an d Le sso n s Le arn e d fro m
Pro gram m atic Ex p e rie n ce

Irvin g Sivin , Harold Nash , an d San d ra Wald m an

P O P U L A T I O N C O U N C I L N E W Y O R K
Library of Congress Cataloging-in-Publication Data

Sivin , Irvin g.
Jadelle levon orgestrel rod im plan ts : a su m m ary of scien tic data an d lesson s learn ed from program m atic experien ce /
Irvin g Sivin , Harold Nash , an d San dra Waldm an .
p. cm .
In clu des bibliograph ical referen ces.
ISBN 0-87834-105-6 (pbk. :alk. paper)
1. Levon orgestrel in trau terin e con traceptives 2. Con traceptive dru g im plan ts. 3. Norgestrel. 4. Birth con trol.
5. Con traceptives. 6. Wom en —Health an d h ygien e. I. Nash , Harold. II. Waldm an , San dra. III. Title.

RG137.35.L5 S59 2002

615’.766—dc21
2002016912

Norplan t ® is th e registered tradem ark of th e Popu lation Cou n cil for levon orgestrel su bderm al im plan ts.
Jadelle ® is th e registered tradem ark of Leiras Ph arm aceu ticals (Tu rku , Fin lan d) for levon orgestrel rods.

Irvin g Sivin , MA, an d Haro ld N ash , Ph .D., are sen ior scien tists at th e Popu lation Cou n cil’s Cen ter for Biom edical Research .
San d ra Wald m an , MS, was director of pu blic in form ation at th e Popu lation Cou n cil.

Th is pu blication was m ade possible th rou gh su pport provided by th e Office of Popu lation , Bu reau for
Global Program s, Field Su pport & Research , U.S. Agen cy for In tern ation al Developm en t, u n der th e term s of
Cooperative Agreem en t No. CCP-A-00-94-00013. Th e opin ion s expressed h erein are th ose of th e au th ors
an d do n ot n ecessarily reflect th e views of th e U.S. Agen cy for In tern ation al Developm en t.

Y E A R S
1952–2002

Th e Popu lation Cou n cil is an in tern ation al, n on profit, n on govern m en tal in stitu tion th at seeks to im prove
th e well-bein g an d reprodu ctive h ealth of cu rren t an d fu tu re gen eration s arou n d th e world an d to h elp ach ieve a
h u m an e, equ itable, an d su stain able balan ce between people an d resou rces. Th e Cou n cil con du cts biom edical,
social scien ce, an d pu blic h ealth research an d h elps bu ild research capacities in developin g cou n tries. Establish ed in 1952,
th e Cou n cil is govern ed by an in tern ation al board of tru stees. Its New York h eadqu arters su pports a global n etwork of
region al an d cou n try offices.

Popu lation Cou n cil

On e Dag Ham m arskjold Plaza
New York, New York 10017 USA
212/ 339-0500; fax 212/ 755-6052
e-m ail: pu bin fo@popcou n cil.org
h ttp:/ / www.popcou n cil.org

©2002 Th e Popu lation Cou n cil, In c.

Prin ted in th e Un ited States of Am erica
CON TEN TS
ACKNOWLEDGMENTS ......................................iv
ABOUT THIS MONOGRAPH................................v
DEVELOPMENT AND INTRODUCTION
OF CONTRACEPTIVE IMPLANTS........................1
Research an d developm en t ..................................1
In trodu ction activities ..........................................2
Cou n tries with Norplan t an d
Jadelle experien ce, 1980–2001 ........................4
Ch ron ology of im portan t even ts
in th e developm en t of Norplan t
an d Jadelle, 1966–2001 ....................................5
HIGHLIGHTS OF CLINICAL PERFORMANCE
OF JADELLE IMPLANTS......................................7
Su m m ary of ch aracteristics ..................................7
Com pon en ts ........................................................7
Preclin ical evalu ation ..........................................8
Clin ical overview ................................................10
Metabolic effects ................................................16
Su m m in g u p ......................................................18
RECOMMENDATIONS FOR INTRODUCING
JADELLE INTO DEVELOPING-COUNTRY
FAMILY PLANNING PROGRAMS:
LESSONS LEARNED FROM THE
NORPLANT EXPERIENCE..................................19
ANSWERS TO FREQUENTLY ASKED
QUESTIONS ABOUT JADELLE..........................22
Gen eral in form ation ..........................................22
In sertion an d rem oval ........................................24
Side effects an d h ealth con sideration s ..............26
Research an d developm en t ................................30
INTERNATIONAL POSTMARKETING
SURVEILLANCE OF NORPLANT ......................32
Major h ealth even ts ..........................................32
Pregn an cies ........................................................33
Oth er reported h ealth problem s ........................33
BIBLIOGRAPHY: NORPLANT IMPLANTS
AND JADELLE RODS ........................................34
FIGURES AND TABLES
Figu re 1. Com position of Jadelle
an d Norplan t ........................................................8
Figu re 2. Stru ctu ral form u la of
levon orgestrel ......................................................8
Table 1. Seru m con cen tration of
levon orgestrel with Jadelle rods ..........................9
Table 2. Com parison of con traceptive
failu re rates du rin g th e first year of u se ............11
Table 3. Cu m u lative discon tin u ation an d
con tin u ation rates for Jadelle ............................12
Table 4. Men stru al con dition s reported
in clin ical trials of Jadelle ..................................13
Table 5. Adverse reaction s du rin g
five years of Jadelle u se in clin ical trials ............14
A CKN OWLED GMEN TS
Man y people an d organ ization s con tribu ted to th e
m ore th an th ree decades of research , developm en t,
an d in trodu ction of levon orgestrel (LNG) con tracep-
tive im plan ts—both th e Jadelle ® rods an d th e earlier
Norplan t ® capsu les. Colleagu es in th e Popu lation
Cou n cil’s Cen ter for Biom edical Research (CBR) an d
th e In tern ation al Com m ittee for Con traception
Research (ICCR) developed th e im plan t con cept an d
tested th e two m eth ods in clin ical trials. Pu blic
h ealth experts in th e Cou n cil’s In tern ation al
Program s Division field-tested Norplan t in prein tro-
du ction an d acceptability stu dies.
Norplan t capsu le an d Jadelle rod developm en t
an d in trodu ction in volved collaboration am on g a
n u m ber of in tern ation al tech n ical assistan ce agen -
cies, research in stitu tion s in developed an d develop-
in g cou n tries, an d ph arm aceu tical com pan ies—
Leiras Oy in Fin lan d an d Wyeth -Ayerst Laboratories
in th e Un ited States. Oth er prin cipal collaborators in
th e in itial Norplan t capsu le in trodu ction efforts
in clu ded En gen derHealth (form erly AVSC
In tern ation al), Fam ily Health In tern ation al (FHI),
th e Program for Appropriate Tech n ology in Health
(PATH), an d th e World Health Organ ization (WHO).
In vestigators from in tern ation al train in g cen ters as
well as clin ics in m an y cou n tries con tribu ted to th e
wealth of scien tific data th at docu m en t th e Norplan t
m eth od. Th eir work was described in a 1990 m on o-
graph , Norplant® Levonorgestrel Implants: A Summary of
Scientific Data, an d is in clu ded in th e exten sive bibli-
iv
ograph y at th e en d of th is m on ograph . Organ ization s
in volved in Jadelle rod train in g activities in clu de
En gen derHealth , Path fin der, JHPIEGO, an d th e
Popu lation Cou n cil.
Norplan t capsu le an d Jadelle rod research an d
developm en t were su pported by several govern m en t
agencies, foundations, and individuals: the United
States Agency for International Development (USAID)
and the International Development Research Centre of
Canada; the Ford Foundation, the Andrew W. Mellon
Foundation, the Rockefeller Foundation, the George F.
Jewett Fou n dation , th e Gen eral Service Fou n dation ,
an d th e estate/ ch aritable tru st of Abby R. Mau zé; th e
Un ited Nation s Popu lation Fu n d (UNFPA); Mr.
George J. Hech t (an d, after h is death , th e George J.
Hech t Fu n d) an d several m em bers of th e Rockefeller
fam ily; Wyeth -Ayerst Laboratories; an d th e
Popu lation Cou n cil. We gratefu lly ackn owledge su p-
port for th is m on ograph from th e Office of
Popu lation , Bu reau for Global Program s, Field
Su pport & Research , U.S. Agen cy for In tern ation al
Developm en t.
We are in debted to Felice Apter, San dra Arn old,
Marth a Brady, Iren e Bu rke, Dian e D. Harrison ,
Merja Metsä-Heikkilä, Pekka Läh teen m äki, Su ellen
Miller, Kath leen Reape, Mary Sen di, Jeff Spieler,
Kirsten Vogelson g, an d Margaret Weber for th eir
patien t an d frequ en t reviews of th is m on ograph ; an d
to Evan Read, wh o prepared th e figu res an d tables
u sed in th is m on ograph .
A BOUT THIS MON OGRA PH
This scientific monograph provides a comprehensive
summary of the clinical characteristics of Jadelle levo-
norgestrel (LNG) rod implants, as observed during
clinical trials conducted by the Population Council.
The monograph also reviews lessons learned about
how to provide Jadelle, based partly on conclusions
gleaned from the extensive experience with Norplant,
the earlier implant system, and suggests practical ways
in which to introduce Jadelle into family planning
programs. The extensive question-and-answer section
presents some of the scientific information in an easy-
to-understand format that serves as a counseling tool.
The section includes language from the Jadelle prod-
uct labeling and also reflects the postmarketing, as
well as clinical, experience with Norplant. In addition,
the monograph summarizes new results from a five-
year postmarketing study of Norplant in eight devel-
oping countries—information with direct relevance to
Jadelle. Finally, a bibliography documents the exten-
sive published research about contraceptive implants
over more than four decades.
The monograph is written for health care profes-
sionals and policymakers interested in learning more
about Jadelle as a possible addition to the contracep-
tives available in national family planning programs
and in private practice.
v
D EVELOPMEN T A N D IN TROD UCTION OF
CON TRA CEPTIVE IMPLA N TS
Th e Popu lation Cou n cil h as devoted m ore th an 30 1978, and later of C. Wayne Bardin, who succeeded
years to th e in ven tion , developm en t, an d in trodu c- Segal and served as director through 1995. The cur-
tion of con traceptive im plan ts—Norplan t* capsu les rent director is Elof Johansson, who was a member of
an d Jadelle* rods. Th rou gh th is exten ded u n dertak- the ICCR when implant research was initiated.
in g, th e Cou n cil n ot on ly developed a n ew form of
reversible, lon g-actin g con traception bu t also pio- Re se arch an d d e ve lo p m e n t
n eered a carefu l process of n ew m eth od in trodu c-
Th e research an d developm en t program th at pro-
tion , with atten tion to research , train in g, cou n selin g,
du ced con traceptive im plan ts—th e im plan ts h ad n o
an d con su m er in form ation .
bran d n am es u n til th ey becam e produ cts m u ch
Several h u n dred steps wen t in to im plan t in ven -
later—began in 1966 in th e Popu lation Cou n cil’s
tion an d developm en t. Basic research determ in ed
biom edical research laboratories wh en scien tists in i-
th e feasibility of th e con cept: wh ich steroids were
tiated laboratory in vestigation s on th e release of
best su ited for an im plan t system , h ow m an y cap-
steroid h orm on es from silicon e ru bber capsu les.
su les or rods wou ld be n eeded, th e dim en sion s an d
Th eir resu lts sh owed th at th e con tin u ou s release of
th ickn ess of th e im plan t walls an d th e in n er core of
h orm on es cou ld be su stain ed for lon g periods, an d
th e rods, an d th e optim u m release rate an d blood
th at h orm on al effects in an im als cou ld be m ain -
level for safe an d effective con traception . Wyeth -
tain ed for over a year. Th ese resu lts form ed th e basis
Ayerst Laboratories h ad earlier con du cted an im al
of th e im plan t con cept: th at an appropriate con tra-
an d toxicology stu dies on its syn th etic progestin ,
ceptive steroid, placed u n der th e skin in silicone tub-
levon orgestrel, an d Dow Corn in g h ad con du cted
ing, could provide effective contraception for many
an im al stu dies an d h u m an trials with its silicon e ru b-
years, and that a single act of contraceptive acceptance
ber elastom er. Th e Cou n cil also gain ed access in later
could replace more than a thousand days of pill taking
stages of developm en t to Nation al In stitu tes of
(Segal 1983; In tern ation al Developm en t Research
Health toxicology stu dies in volvin g con tin u ou s levo-
Centre 1990).
n orgestrel release by im plan ts in an im al system s.
By late 1974, stu dies h ad been started in
Alth ou gh th e Cou n cil did n ot h ave to du plicate pre-
h u m an s of a six-capsu le con traceptive dru g delivery
viou sly con du cted stu dies, ch allen gin g tasks
system . Several syn th etic h orm on es were com pared
rem ain ed: to con ceive of su bderm al im plan ts as a
an d evalu ated. Th e n ext year a ran dom ized clin ical
m ode of deliverin g con traceptive steroids; to design
trial testin g im plan ts con tain in g th ree differen t h or-
im plan ts with doses presu m ed to preven t pregn an cy;
m on es was in itiated in six cou n tries (Brazil, Ch ile,
an d to con du ct an d an alyze stu dies dem on stratin g
Den m ark, Dom in ican Repu blic, Fin lan d, an d
safety, effectiven ess, an d acceptability.
Jam aica). A six-capsu le im plan t system con tain in g
A team of scientists at the Population Council’s
levon orgestrel em erged as th e best of th e th ree, on
Center for Biomedical Research (CBR) accomplished
th e basis of effectiven ess, clin ical acceptability, an d
the day-to-day development of both Norplant and
safety. Th e dru g’s safety was su pported by exten sive
Jadelle, working closely with the network of clinical
an im al stu dies an d by large-scale h u m an stu dies
investigators of the Council’s International Committee
con du cted by Wyeth -Ayerst Laboratories, wh ich
for Contraception Research (ICCR). The project was
m arketed oral con traceptives con tain in g levo-
under the leadership, first, of Sheldon J. Segal, who
n orgestrel.
was director of biomedical research from 1963 to
Two delivery systems and two variations of
* Norplan t ® is th e registered tradem ark of th e Popu lation capsules and rods
Cou n cil for levon orgestrel su bderm al im plan ts. Jadelle ® is th e
registered trademark of Leiras Pharmaceuticals (Turku, Finland) Alth ou gh th e levon orgestrel capsu les were in clin i-
for levon orgestrel rods. cal trials by 1975 an d appeared to be safe, effective,

1
an d acceptable, scien tists believed th at developm en t
of a m eth od with fewer th an six im plan ts wou ld
m ake in sertion an d rem oval easier an d wou ld th ere-
fore be ben eficial. Wh ile still stu dyin g Norplan t
im plan ts, CBR scien tists fou n d th at a silicon e cover
on a solid rod com posed h alf of levon orgestrel, h alf
of silicon e elastom er, in creased th e rod’s ph ysical
stren gth an d gave a m ore con stan t pattern of steroid
release. By 1977, a sm all trial of rods con tain in g
levon orgestrel was u n derway. Over th e n ext few
years, clin ical ph arm acology stu dies an d clin ical tri-
als were started an d m ech an ized produ ction m eth -
ods for th e rods were worked ou t.
By 1982, CBR scientists working in conjunction
w ith Leiras for in du strial-scale produ ction h ad
designed and produced a new rod system. Using two
4 cm rod implants, this system was designed to release
the same dose of levonorgestrel as did the original six-
capsule system for sustained time periods.
A tech n ical evalu ation of Norplan t by th e World
Health Organ ization in 1984 con clu ded th at th e
im plan ts are an “effective an d reversible lon g-term
m eth od of fertility regu lation .” Th e con traceptive,
th e report said, was “particu larly advan tageou s to
wom en wh o wish an exten ded period of con tracep-
tive protection ” (WHO 1985).
In 1987, as th e Cou n cil prepared a New Dru g
Application (NDA) for th e rod system , th en called
Norplan t-2, produ ction ceased of a com pon en t
(Medical Grade Elastom er 382) critical to th e m an u -
factu re of th e rods. Th e Cou n cil began im m ediately
to reform u late th e rod system , u sin g sim ilar elas-
tom ers th at are safe for h u m an u se. Th u s, work on a
reform u lated Norplan t-2 con tin u ed even as Norplan t
capsu les n eared approval by th e U.S. Food an d Dru g
Adm in istration (FDA).
Th e Norplan t capsu le system also h ad u n der-
gon e ch an ges. Th ere w ere tw o form u lation s of th e
capsu les, on e w ith softer, less den se tu bin g th an th e
oth er. Th e New Dru g Application , su bm itted in
1988, con tain ed data abou t experien ce w ith both
kin ds of tu bin g; earlier testin g h ad been con du cted
w ith th e den ser tu bin g, w h ile later testin g w as con -
du cted w ith th e softer tu bin g th at w as to becom e
th e w orld stan dard. Clin ical stu dies h ad sh ow n
both kin ds of tu bin g to be safe an d effective w ith
diverse grou ps of w om en . Th e FDA approved soft-
tu bin g Norplan t in Decem ber 1990 for u se u p to
2
five years. In 2000, th e Popu lation Cou n cil pu b-
lish ed data sh ow in g th at Norplan t w as safe an d
effective for u p to seven years (Sivin , Mish ell, Diaz
et al. 2000). Th e data w ere su bm itted to th e FDA in
Decem ber 2000.
An estim ated 10.5 m illion sets of im plan ts h ave
been distribu ted worldwide sin ce Norplan t wen t on
th e m arket in 1984. Norplan t h as ach ieved regu lato-
ry approval in m ore th an 60 cou n tries.
Stu dies com parin g Norplan t an d th e n ew, refor-
m u lated levon orgestrel rods were in itiated in 1990.
Th e trial, wh ich in volved 2,800 wom en in seven
cou n tries, w as su pported by Wyeth -Ayerst
Laboratories (th e U.S. distribu tor of th e Norplan t
system ), USAID, th e Mellon Fou n dation , an d
UNFPA. A su bm ission for FDA approval of th e rods
as a m eth od for th ree years’ u se was filed in Ju n e
1995. Alth ou gh FDA approval for m arketin g was
gain ed in 1996, th e clin ical trial con tin u ed to gath er
data on effectiven ess an d safety for u p to five years’
u se. In Ju ly 2001, th e FDA gave ten tative approval
for exten sion of th e period of u se to five years. In
Fin lan d, regu latory au th orities approved th e rods—
n ow called Jadelle—for th ree years in 1997 an d, in
2000, exten ded th e period of u se to five years. In
2001, Jadelle was approved as a five-year m eth od in
Fran ce, Icelan d, Lu xem bou rg, th e Neth erlan ds,
Norway, Spain , an d Sweden . Jadelle is approved as a
th ree-year m eth od in In don esia an d Th ailan d.
In tro d u ctio n activitie s
By 1980, with laboratory research an d developm en t
of Norplan t capsu les essen tially com pleted, th e
Cou n cil began to address som e of th e issu es critical
to th e in trodu ction of th e m eth od, to en su re th at
th e n ew con traceptive wou ld be offered in a bal-
an ced an d cu ltu rally sen sitive way (Spiceh an dler
1988). Th e en d of Norplan t developm en t an d th e
begin n in g of in trodu ction overlapped by several
years: th e early 1980s in clu ded trials to gain addi-
tion al data for regu latory filin gs in som e cou n tries
an d th e special prein trodu ction stu dies th at are a
h allm ark of th e Cou n cil’s in trodu ction of th e
m eth od. From a m edical stan dpoin t, th e im plan t
system is a very sim ple m eth od: lon g-actin g, effec-
tive, con ven ien t, an d reversible. Bu t, from a service
delivery perspective, im plan ts are com plicated
becau se m u ch depen ds on th e preparation s a fam ily
plan n in g program m akes before th e first set of cap-
su les or rods is in serted in to th e first wom an ’s arm .
Th at is wh ere th e con traceptive in trodu ction pro-
gram played an im portan t role.
In trodu ction activities in clu ded su pport for th ree
in tern ation al train in g cen ters: in -cou n try train in g of
h ealth care providers; developm en t of prototype
in form ation al m aterials; an d u ser-related research .
Followin g in corporation of im plan ts in to n ation al
fam ily plan n in g program s, th e Cou n cil worked with
h ealth m in istries an d oth er organ ization s to assess
h ow services h ave been provided an d h ow th ey
cou ld be im proved.
Norplant preintroduction studies
Workin g with oth er agen cies, th e Cou n cil in itiated a
series of prein trodu ction trials—altogeth er m ore th an
30—to evalu ate th e effectiven ess, safety, an d accept-
ability of th e m eth od u n der local con dition s.
Prein trodu ction stu dies w ere an in n ovation of
Norplan t im plan t in trodu ction . Th ey h elped n ation al
program s an d h ealth care providers evalu ate th e
m eth od in specific settin gs an d provided a m ech a-
n ism to tran sfer th e train in g skills for proper u se of
th e m eth od. Wh ere local experien ce was requ ired for
regu latory approval, th e stu dies provided data to fu r-
th er in form govern m en tal au th orities abou t th e
m eth od. Th ey provided a basis for assessm en t of u ser
an d program m atic n eeds in differen t cu ltu ral an d
socioecon om ic situ ation s. Th ey also served as a
way to develop an d test local m an agem en t practices
for respon sible in corporation of th e m eth od in to fam -
ily plan n in g program s an d to dissem in ate in for-
m ation al m aterials.
Introduction of Jadelle
Becau se of th e exten sive experien ce with im plan ts in
m an y cou n tries, Jadelle does n ot n eed to u n dergo
th e sam e kin d of prein trodu ction stu dies as Norplan t
did. In form ation is n eeded, h owever, on h ow fam ily
plan n in g program s th at already provide Norplan t can
m ake th e tran sition to offerin g Jadelle. Th e Cou n cil
in collaboration with local partn ers in itiated tran si-
tion stu dies in th e Dom in ican Repu blic an d
Gu atem ala. Th e Dom in ican Repu blic h as h ad a su c-
cessfu l im plan t program for years, wh ile Gu atem ala
h as offered Norplan t on ly for th e past year.
Th ese tran sition stu dies were design ed to discover
th e best ways fam ily plan n in g program s can provide
Jadelle. Th e stu dies will evalu ate th e system readi-
n ess, train in g requ irem en ts, clin ical perform an ce,
an d acceptan ce of Jadelle im plan ts wh en offered as
an addition al con traceptive option , or as an option i
n place of Norplan t. In th is way, fam ily plan n in g
providers, program m an agers, an d plan n ers can
begin to develop kn owledge of h ow to en su re a
sm ooth tran sition to n ewer tech n ologies. Th e stu dies
will provide key in form ation abou t wh ich in ter-
ven tion s are n ecessary to prepare th e service delivery
system to provide Jadelle with th e h igh est qu ality
services.
Th e tran sition stu dies will n ot on ly provide
in form ation to register Jadelle in th ese two cou n -
tries, th ey will also determ in e wh eth er th e service
delivery system s are ready to offer im plan ts with
h igh -qu ality care an d establish w h at activities
sh ou ld be added or altered to optim ize th e in trodu c-
tion of Jadelle. Fin ally, th e stu dies will exam in e th e
im pact of th e addition of a n ew, reversible im plan t-
able h orm on al m eth od on th e total acceptan ce of
reversible m eth ods, as well as th e in flu en ce of th e
in trodu ction of Jadelle on th e qu ality of con tracep-
tive services.
Lesson s learn ed from th e in trodu ction of
Norplan t capsu les in to differen t h ealth delivery sys-
tem s h ave accen tu ated th e n eed for train in g of
providers in in sertion an d rem oval tech n iqu es an d
cou n selin g; provision of fu ll in form ation th rou gh
cou n selin g an d in form ation al m aterials for clien ts on
im plan ts an d oth er available con traceptive m eth ods;
su pervision of providers; developm en t an d im ple-
m en tation of a clien t-trackin g system ; an d on goin g
program evalu ation . For m ore in form ation , see th e
section in th is m on ograph titled “Recom m en dation s
for in trodu cin g Jadelle in to developin g-cou n try fam -
ily plan n in g program s: Lesson s learn ed from th e
Norplan t experien ce.”
In cou n tries with n o prior experien ce with
Norplan t im plan ts, th e Cou n cil an d oth er grou ps will
h elp evalu ate th e n eeds of wom en for a lon g-actin g
con traceptive m eth od an d th e ability of th e h ealth
delivery system s to provide im plan t services with th e
h igh est qu ality possible. Th e cou n tries th at partici-
pated in Norplan t an d Jadelle trials an d oth er stu dies
are listed on page 4.
3
Co u n trie s w ith N o rp lan t an d Jad e lle e x p e rie n ce , 1980–2001
N o rp lan t clin ical trials: 13 co u n trie s
Brazil, Ch ile, Den m ark, Dom in ican Repu blic,
Fin lan d, Jam aica, Sweden , Un ited States
(PC/ ICCR);* Colom bia, Ecu ador, Egypt, In don esia,
Th ailan d (PC)
Jad e lle clin ical trials: 7 co u n trie s
Ch ile, Dom in ican Repu blic, Egypt, Fin lan d,
Sin gapore, Th ailan d, Un ited States (PC/ ICCR)
N o rp lan t p re in tro d u ctio n stu d ie s:
30 co u n trie s, 1984 th ro u gh 1990
Ban gladesh , Brazil, Ch ile, Ch in a, Dom in ican
Repu blic, Haiti, Ken ya, Nepal, Nigeria, Ph ilippin es,
Sin gapore, Sri Lan ka, Zam bia (1984–85); Colom bia,
El Salvador, Gh an a, Malaysia, Mexico, Pakistan ,
Peru , Sen egal, Sou th Korea, Tu n isia, Ven ezu ela,
Zam bia (1986–88); Bah am as, Rwan da, Zaire (1989);
Bolivia, Madagascar (1990)
Jad e lle tran sitio n stu d ie s:
2 co u n trie s (startin g 2001)
Dom in ican Repu blic, Gu atem ala
N o rp lan t p rivate -se cto r train in g:
8 co u n trie s
Belgiu m , Bu lgaria, Fran ce, Israel, Soviet Un ion ,
Taiwan , West Germ an y (Leiras, 1988); Un ited States
(Wyeth -Ayerst, 1990)
N o rp lan t p o stm ark e tin g su rve illan ce :
8 countrie s (UNDP/UNFPA/WHO/HRP,*
Population Council, FHI*)
Ban gladesh , Ch ile, Ch in a, Colom bia, Egypt,
In don esia, Sri Lan ka, Th ailan d
N o rp lan t train in g cu rricu lu m te stin g:
3 co u n trie s
Ken ya, Nigeria, Rwan da
N o rp lan t in te rn atio n al train in g ce n te rs:
3 co u n trie s
Dom in ican Repu blic, Egypt, In don esia
4
N o rp lan t re gio n al train in g ce n te r: 1 co u n try
Ken ya
N o rp lan t acce p tability stu d ie s: 20 co u n trie s
(Po p u latio n Co u n cil, PATH,* FHI)
Ban gladesh , Brazil, Ch in a, Colom bia,
Dom in ican Repu blic, Ecu ador, Egypt, Haiti,
In don esia, Ken ya, Mexico, Nepal, Nigeria,
Peru , Ph ilippin es, Rwan da, Sri Lan ka, Th ailan d,
Un ited States, Zam bia
N o rp lan t re gu lato ry ap p ro vals:
62 co u n trie s sin ce 1983
Bah rain , Ban gladesh , Botswan a, Bu rkin a Faso,
Can ada, Ch ile, Ch in a, Colom bia, Costa Rica, Cypru s,
Czech Repu blic, Dom in ican Repu blic, Ecu ador,
Egypt, Eth iopia, Fin lan d, Fran ce, West Germ an y,
Gh an a, Greece, Haiti, In don esia, Iran , Israel,
Jam aica, Jordan , Ken ya, Ku wait, Lu xem bou rg,
Madagascar, Malawi, Malaysia, Mali, Mau ritiu s,
Mexico, Nepal, Neth erlan ds, Nigeria, Pakistan ,
Palau , Peru , Ph ilippin es, Ru ssia, Rwan da, Sen egal,
Sin gapore, Slovak Repu blic, Sou th Africa, Sri Lan ka,
Sweden , Switzerlan d, Syrian Arab Repu blic, Taiwan ,
Tan zan ia, Th ailan d, Ugan da, Un ited Kin gdom ,
Un ited States, Ven ezu ela, Vietn am , Zam bia,
Zim babwe
Jad e lle re gu lato ry ap p ro vals: 11 co u n trie s
Un ited States (1996); Fin lan d (1997); In don esia,
Th ailan d (2000); Fran ce, Icelan d, Lu xem bou rg,
Neth erlan ds, Norway, Spain , Sweden (2001)
*Collaboratin g organ ization s:
PC: Popu lation Cou n cil an d th e ICCR: In tern ation al
Com m ittee for Con traception Research
FHI: Fam ily Health In tern ation al
PATH: Program for Applied Tech n ology in Health
UNDP/ UNFPA/ WHO/ HRP: World Health
Organ ization / World Ban k Special Program m e of
Research , Developm en t an d Research Train in g in
Hu m an Reprodu ction
Ch ro n o lo gy o f im p o rtan t e ve n ts in th e d e ve lo p m e n t o f
N o rp lan t an d Jad e lle , 1966–2001
(Even ts related to Jadelle are in dicated in italicized type)

1966 Research an d developm en t program begin s 1984– Prein trodu ction trials begin in Ban gladesh ,
in the laboratories of the Population Council. 1985 China, Ghana, Haiti, Kenya, Nepal, Nigeria,
Philippines, Sri Lanka, and Zambia. Ecuador,
1968 First clin ical experien ce with a progestin
Indonesia, and Sweden approve Norplant.
released from silicon e ru bber capsu les is
Th e In tern ation al Plan n ed Paren th ood
reported in San tiago, Ch ile.
Federation in clu des Norplan t on th e com -
1974 Six-capsu le silicon e ru bber dru g delivery m odities list m ade available to its affiliates.
system is developed. First clin ical stu dies
1986– Norplan t is approved by Colom bia,
begin in Ch ile. Work proceeds on levonorgestrel
1987 Dom in ican Repu blic, Peru , Sri Lan ka,
(LNG) rod implants.
Th ailan d, an d Ven ezu ela.
1975 Mu ltin ation al Ph ase 3 trial of capsu le
1988 Norplan t is approved by Ch ile. Th e
m eth od is in itiated in Brazil, Ch ile,
Popu lation Cou n cil files for U.S. FDA
Denmark, Dominican Republic, Finland, and
approval of Norplan t. Five-year postm ar-
Jamaica. Trial is monitored by the Population
ketin g su rveillan ce of Norplan t capsu les is
Cou n cil’s In tern ation al Com m ittee for
started in eigh t developin g cou n tries.
Contraception Research (ICCR).
1989– Norplan t is approved in Ban gladesh , Ch in a,
1977 Limited trial of LNG rod begins.
1990 Czech Repu blic, Haiti, Ken ya, Malaysia,
1980– Trials of Norplant capsules begin in Colombia Nepal, Sin gapore, an d Tu n isia. Norplan t is
1982 Ecu ador, Egypt, In dia, In don esia, an d approved in th e Un ited States in Decem ber
Th ailan d. Ph ase 2 an d 3 an d clin ical ph ar- 1990.
m acology stu dies begin in th e Un ited
1990 Jadelle clinical trials begin in Chile, Dominican
States. Multinational clinical trial comparing
Republic, Egypt, Finland, Singapore, Thailand,
Norplant and LNG rods (original version)
and United States.
begins in Chile, Dominican Republic, Finland,
Sweden, and United States. 1991– Norplan t is approved in Jam aica, Mali,
1992 Mau ritiu s, Mexico, Pakistan , Palau , Ru ssia,
1983 Leiras Oy, of Fin lan d, is licen sed to m an u -
Rwan da, an d Taiwan .
factu re an d distribu te Norplan t capsu les.
Fin lan d becom es th e first cou n try to give 1993– Norplan t is approved in Bah rain , Can ada,
regu latory approval to th e m eth od. 1994 Costa Rica, Egypt, Fran ce, Gh an a, Iran ,
Lu xem bou rg, Madagascar, Malaw i,
1984 Th e World Health Organ ization (WHO)
Ph ilippin es, Rom an ia, Sen egal, Sou th
evalu ates th e Norplan t m eth od in respon se
Africa, Tan zan ia, an d Un ited Kin gdom .
to a requ est for a tech n ical evalu ation by
th e Un ited Nation s Popu lation Fu n d 1995 Application for approval of Jadelle is made to the
(UNFPA). WHO con clu des th at Norplan t U.S. Food and Drug Administration.
im plan ts are an “effective an d reversible
lon g-term m eth od of fertility regu lation ...
particu larly advan tageou s to wom en wh o
wish an exten ded period of con traceptive
protection .”
continued

5
Ch ro n o lo gy (continued)
1995– Norplan t capsu les are approved in Bu rkin a
1996 Faso, Cypru s, Den m ark, Greece, Germ an y,
Israel, Ku wait, Neth erlan ds, Switzerlan d,
Zam bia, an d Zim babwe. Jadelle is approved
2001
in the United States as a three-year method.
1997 Jadelle is approved in Finland as a three-year
method.
2000 Jadelle use is extended to five years’ use in
Finland and for three years’ use in Indonesia
and Thailand. The U.S. FDA is asked to extend
Jadelle use to five years. Leiras introduces its pre-
6
loaded, disposable inserter for Jadelle. Th e
Cou n cil su bm its seven -year data for
Norplan t to th e FDA.
Jadelle is approved for five years’ use in France,
Iceland, Luxembourg, Netherlands, Norway,
Spain, and Sweden. In July, the FDA sends an
approvable letter extending Jadelle use to five
years in the United States. Jadelle transition
studies begin in the Dominican Republic and
Guatemala.
HIGHLIGHTS OF CLIN ICA L PERFORMA N CE OF
JA D ELLE IMPLA N TS

Su m m ary o f ch aracte ristics

Indications: lon g-term reversible
m eth od of con traception in di-
cated for preven tion of preg-
n an cy
Active ingredient: levon orgestrel
Annual pregnancy rate per 100 users
in clinical trials: 0.1 for each of
years 1 through 3, 0 for year 4,
0.8 for year 5
Cumulative pregnancy rate in clinical
trials: 3 years: 0.3; 5 years: 1.1
Duration of use: 5 years (Fin lan d
an d oth er Eu ropean cou n -
tries); 3 years (Un ited States,
bu t th e FDA in Ju ly 2001 in di-
cated exten din g du ration of
u se to 5 years is approvable
su bject to agreem en t on label-
in g an d qu ality assu ran ce con -
cern s)
Release rate: 100 µg/ day at 1
m on th , declin in g to abou t 40
µg/ day at 12 m on th s, an d sta-
bilizin g at abou t 30 µg/ day at
24 m on th s an d th ereafter
Return to fertility: In th e year fol-
lowin g rem oval, pregn an cy
rates are com parable to th ose
for wom en of sim ilar age u sin g
n o con traception
Continuation rates in clinical trials:
1 year: 88.3 per 100; 3 years:
60.6 per 100; 5 years: 41.5 per
100; average u se 3.35 years
th rou gh th e en d of 5 years
Mechanisms of action: in h ibition of
ovu lation , th icken in g of cervi-
cal m u cu s
Most frequently reported side effects:
In addition to bleedin g irregu -
larities, 10 percen t or m ore of
wom en in clin ical trials report-
ed th ese adverse reaction s:
h eadach e, dizzin ess, weigh t
gain , in fection / pain at im plan t
site, leu korrh ea, m astalgia,
n au sea, pelvic pain , u rin ary
tract sym ptom s/ in fection , an d
vagin itis. Oth er frequ en tly
reported side effects related to
Jadelle u se were n ervou sn ess;
acn e, h air loss, an d oth er skin
an d h air disorders; an d ovarian
cyst or follicle en largem en t
(see Table 5 for addition al
adverse even ts).
Clinical pharmacology: n o clin ically
sign ifican t u n favorable ch an ges
in liver, kidn ey, adren al, or
th yroid fu n ction . Lipoprotein s:
decreases in total ch olesterol,
LDL ch olesterol, HDL ch oles-
terol, an d triglycerides bu t n o
clin ically sign ifican t ch an ge in
ratio of HDL to total ch oles-
terol
Contraindications: kn own or su s-
pected pregn an cy; active
th rom boph lebitis or th rom -
boem bolic disorders; u n diag-
n osed abn orm al gen ital bleed-
in g; acu te liver disease, ben ign
or m align an t liver tu m ors;
kn own or su spected breast
can cer; h istory of idiopath ic
in tracran ial h yperten sion ;
h ypersen sitivity to levo-
n orgestrel or an y of th e com -
pon en ts of Jadelle
Provision: rods are in serted u n der
th e skin in th e wom an ’s u pper
arm th rou gh a sm all in cision
an d are rem oved th rou gh th e
sam e in cision
STD protection: n o kn own protec-
tion again st HIV/ AIDS or oth er
sexu ally tran sm itted
diseases

Co m p o n e n ts ru bber tu bin g an d sealed at each en d by polydi-

Jadelle is a set of two flexible cylin drical im plan ts
con sistin g of a dim eth ylsiloxan e/ m eth ylvin ylsiloxan e
copolym er core en closed in th in -walled silicon e tu b-
in g. Each rod con tain s 75 m g of th e progestin levo-
n orgestrel. Th e core of each rod is a m ixtu re, h alf of
levon orgestrel, h alf of th e elastom er. Th e rods are
sealed with polydim eth ylsiloxan e adh esive an d ster-
ilized. Each rod is approxim ately 2.5 m m in diam eter
an d 43 m m in len gth .
By com parison , th e Norplan t system con sists of
six flexible silicon e capsu les con tain in g levo-
n orgestrel in dry, crystallin e form packed with in th e
m eth ylsiloxan e m edical adh esive an d sterilized. Each
capsu le con tain s 36 m g of levon orgestrel an d is 2.4
m m in diam eter an d 34 m m lon g (see Figu re 1).
Jadelle is a progestin -on ly produ ct an d does n ot
con tain estrogen . Th e sole active in gredien t in th e
rods is levon orgestrel (-)-13-eth yl-17-h ydroxy-18,
19-din or-17α-pregn -4-en -20-yn -3-on e. It h as a m ol-
ecu lar weigh t of 312.45 an d th e stru ctu ral form u la
sh own in Figu re 2.
Medical grade silicon e ru bber m aterials, in clu d-
in g th e type u sed in Jadelle, h ave been em ployed in
variou s im plan table devices for h u m an s sin ce 1950.

7
Th ese im plan ts h ave in clu ded prosth etic devices,
Figu re 1. Co m p o sit io n o f Jad e lle
h eart valves, an d drain age tu bes. Silicon e ru bber was an d N o rp lan t
ch osen for u se in Norplan t capsu les an d Jadelle rods
J ad elle rod Norp lan t cap su le
becau se it is soft an d flexible. Levon orgestrel diffu ses
m edical m edical
th rou gh it at a rate th at delivers an appropriate con -
adh esive adh esive
traceptive dose over a period of years; th ere is lon g
th in -w alled silicon e

34 m m
experien ce with its u se in con tact with tissu es.
silicon e tu bin g tu bin g

43 m m
levon orgestrel levon orgestrel
Pre clin ical e valu atio n an d a siloxan e
Pharmacology copolym er

Levon orgestrel is a totally syn th etic an d biologically

active progestin th at exh ibits n o sign ifican t estro-
gen ic activity an d is h igh ly progestation al. It is th e
progestation al in gredien t in m an y oral con tracep-
tives. Th e absolu te con figu ration con form s to th at of
D-n atu ral steroids. Levon orgestrel delivered su bder-
m ally is n ot su bject to a “first-pass” effect th rou gh
th e liver an d is virtu ally 100 percen t bioavailable
(Back, Bates, Brecken ridge et al. 1989; Hu m pel,
Wen dt, Pom m eren ke et al. 1978).
Release rates of levonorgestrel
Release of levon orgestrel su fficien t to preven t con -
ception is reach ed with in 24 h ou rs after placem en t
of th e rods an d is m ain tain ed at an effective rate for
five years. First-m on th pregn an cies m ay occu r if th e
im plan ts are placed su fficien tly late in th e follicu lar
stage so th at ovu lation is n ot blocked.
Diffu sion of levon orgestrel from th e rods pro-
vides a con tin u ou s low dose of th e progestin .
Resu ltin g blood con cen tration s are su bstan tially
below th ose gen erally observed am on g u sers of com -
bin ation oral con traceptives con tain in g th e pro-
gestin s n orgestrel or levon orgestrel.
Th e calcu lated m ean in vivo release rate of levo-
n orgestrel provided by Jadelle is abou t 100 µg/ day at
on e m on th , declin in g to abou t 40 µg/ day at 12
m on th s an d to abou t 30 µg/ day at 24 m on th s, stabi-
lizin g th ereafter at abou t 30 µg/ day (Leiras 2000).
Blood levels
Levon orgestrel is delivered directly in to in terstitial
flu ids from th e su bcu tan eou s im plan ts. However, th e
bioavailability of levon orgestrel after in sertion of
Jadelle rods com pared with in traven ou s adm in istra-
tion is n ot kn own . After placem en t of Jadelle rods,
levon orgestrel con cen tration s reach a m axim u m , or
n ear m axim u m , level with in two to th ree days after
2.4 m m
2.5 m m
Figu re 2. St ru ct u ral fo rm u la o f
le v o n o rge st re l
CH3 OH
C CH
H H
H H
O
placem en t, with m ean valu es of 772 ± 414 pg/ m L at
two days (Sivin , Läh teen m äki, Ran ta et al. 1997).
Th ey declin e rapidly over th e first m on th both
becau se of a decrease in th e rate of release an d
becau se of decreased circu latin g levels of sex h or-
m on e bin din g globu lin (SHBG), a protein th at bin ds
levon orgestrel. Mean levon orgestrel con cen tration s
slowly declin e to 435 ±172 pg/ m L at on e m on th (see
Table 1), 357±155pg/ m L at six m on th s, an d 280±123
pg/ m L at th ree years. Con cen tration s at fou r an d five
years are sim ilar to th ose at th ree years (Sivin , Wan ,
Ran ta et al. 2001).
Seru m levon orgestrel con cen tration s sh ow con -
siderable variation am on g wom en , depen din g on
in dividu al m etabolic clearan ce rates, body weigh t,
an d oth er factors. Seru m con cen tration s alon e are
n ot predictive of th e risk of pregn an cy in an in divid-
u al wom an . Levon orgestrel con cen tration s in Jadelle
u sers are su bstan tially below th ose gen erally
observed in u sers of oral con traceptives con tain in g
n orgestrel or levon orgestrel.

8
 Excretion
Table 1. Se ru m co n ce n tratio n o f
After rem oval of th e im plan ts, levon orgestrel con -
le vo n o rge stre l w ith Jad e lle ro d s
cen tration s decrease below 100 pg/ m L by 96 h ou rs
Tim e after
an d below sen sitivity of th e assay by five days to two
p lacem en t M ean ± SD
weeks. Th e elim in ation h alf-life of levon orgestrel is
(m on th s) (p g/ m L) n
approxim ately 13 to 18 h ou rs (Sisen win e, Kim m el,
1 435 ± 172 181
Liu et al. 1975). Levon orgestrel an d its m etabolites
3 393 ± 191 165
are prim arily excreted in th e u rin e (40 percen t to 68
6 357 ± 155 160
percen t) an d a lesser am ou n t in th e feces (16 percen t
12 340 ± 159 148
to 48 percen t).
24 312 ± 153 126
36 280 ± 123 89 Mechanisms of action
48 271 ± 126 67
Th e m ech an ism s of action of Norplan t capsu les an d
60 279 ± 123 65
Jadelle are th e sam e, sin ce th e two dosage form s pro-
vide com parable levon orgestrel blood levels after th e
first week of u se. At least two m ech an ism s are active
Levon orgestrel seru m con cen tration s are
in preven tin g pregn an cy: ovu lation in h ibition an d
in versely related to body weigh t. For exam ple,
th icken in g of th e cervical m u cu s, th u s preven tin g
seru m levon orgestrel con cen tration s in w om en
passage of sperm in to th e u teru s. Oth er m ech an ism s
weigh in g m ore th an 70 kg were approxim ately h alf
m ay add to th ese con traceptive effects.
th ose in wom en weigh in g less th an 50 kg (Affan di,
Stu dies were con du cted to evalu ate th e effects of
Su h erm an , Djajalelan a et al. 1987; Foth erby 1995).
Norplan t u se on cervical m u cu s. As h as been report-
It h as been su ggested th at som e in dividu al varia-
ed for u sers of progestin -on ly m in ipills, th e cervical
tion s—possibly fibrou s en capsu lation , local capillari-
m u cu s collected from im plan t u sers was fou n d to be
ty, or local body fat—m ay redu ce levon orgestrel
th ick an d im perm eable even if th e u sers were regu -
release from th e im plan ts. Wom en vary in th eir rates
larly m en stru atin g, th ereby h am perin g sperm m obil-
of levon orgestrel m etabolism an d in th eir levels of
ity. Th is is believed to explain h ow Jadelle protects
SHBG th at bin d to levon orgestrel (Wein er an d
again st pregn an cy even wh en a wom an is ovu latin g.
Joh an sson 1976).
In vitro exam in ation sh owed sperm pen etration to be
Distribution m arkedly poorer in m u cu s collected from im plan t
Levon orgestrel in seru m is prim arily protein bou n d. u sers th an in m u cu s from th e m atch ed con trol su b-
Approxim ately h alf is bou n d to albu m in an d a little jects n ot u sin g h orm on al con traceptives.
less is bou n d to sex h orm on e bin din g globu lin . SHBG In an oth er im plan t u ser stu dy in wh ich post-
con cen tration s are depressed by levon orgestrel with - coital tests were perform ed, resu lts in dicated th at
in a few days of adm in istration , with resu ltan t few sperm reach ed th e cervical can al, an d th ose th at
decreases in circu latin g levon orgestrel con cen tra- did were of redu ced m otility. Microscopic observa-
tion s. tion s of th e m orph ology of im plan t u sers’ cervical
m u cu s were also con sisten t with th e preven tion of
Metabolism con ception (Brach e, Fau n des, Joh an sson et al. 1985;
Levon orgestrel m etabolic path ways h ave been on ly Croxatto, Diaz, Salvatierra et al. 1987). An an alysis
partially delin eated. 16ß -h ydroxylation is an iden ti- of ch an ges in cervical m u cu s followin g Norplan t
fied path w ay of m etabolism . Con cen tration s of in sertion sh owed a rapid declin e in m u cu s receptivi-
m etabolites in circu lation soon exceed th ose of levo- ty to sperm (Du n son , Blu m en th al, Alvarez et al.
n orgestrel, m ostly as con ju gated su lfates. Metabolic 1998).
clearan ce rates m ay differ am on g in dividu als by sev- In stu dies to determ in e th e exten t of ovu lation
eral fold; th is fact is believed to accou n t in part for su ppression occu rrin g with levon orgestrel im plan t
th e wide variation observed in levon orgestrel seru m u se, blood sam ples were drawn from u sers twice a
con cen tration s am on g im plan t u sers. week for five or six con secu tive weeks. Sam ples

9
were classified as com patible with ovu lation if a pro-
gesteron e level above 9.5 n an am oles (n M) per liter
was dem on strated in at least on e sam ple an d was
im m ediately followed or preceded by on e or m ore
sam ples with valu es above 6.4 n M per liter.
Levon orgestrel, at th e average dose of 30 µg per
day as delivered su bderm ally, was sh own to su ppress
ovu lation in abou t 50 percen t of th e cycles stu died
(Croxatto, Diaz, Salvatierra et al. 1987; Brach e,
Alvarez-San ch ez, Fau n des et al. 1990). Even wh en
progesteron e levels rise above th ose th at are con -
ven tion ally taken as sign alin g ovu lation , m ean levels
are below th ose fou n d in n orm ally ovu latin g wom en
w h o w ere n ot u sin g h orm on al con traceptives
(Brach e, Fau n des, Joh an sson et al. 1985; Brach e,
Alvarez-San ch ez, Fau n des et al. 1990; Brach e,
Alvarez-San ch ez, Fau n des et al. 1992). Th is devia-
tion from n orm al h orm on e pattern s m ay con tribu te
to con traceptive effect (Fau n des, Brach e, Tejeda et
al. 1991; Brach e, Fau n des, Joh an sson et al. 1985;
Olsson an d Odlin d 1988).
An oth er stu dy (Segal, Alvarez-San ch ez, Brach e
et al. 1991) assessed h u m an ch orion ic gon adotropin
(HCG) levels in wom en u sin g Norplan t an d wom en
n ot u sin g a con traceptive an d attem ptin g to con -
ceive. (HCG appears in blood soon after im plan ta-
tion .) Am on g wom en in th e con trol grou p, n in e h ad
eviden ce of HCG produ ction an d six advan ced to
clin ical pregn an cies. In 13 cycles ju dged by proges-
teron e levels to be ovu latory in th e Norplan t grou p,
HCG was n ot detected.
Toxicology
Toxicology stu dies in an im als h ave been con du cted
u sin g both su bderm al im plan ts an d oral adm in istra-
tion of levon orgestrel (Nash 1990). Th e stu dies u sin g
su bderm al im plan ts su pplied doses 14 an d 56 tim es
th e h u m an dose on a body weigh t basis to m on keys
an d 80 tim es th e h u m an dose on a body weigh t basis
to rats. Effects on organ s in both th e oral an d th e
im plan t an im al safety stu dies were largely th ose
expected of progestation al agen ts.
Th e an im al stu dies u sin g th e oral rou te of
adm in istration h ave served as a basis for U.S. Food
an d Dru g Adm in istration approval as safe of oral
con traceptives con tain in g (a) dl-n orgestrel or levo-
n orgestrel in com bin ation with eth yn ylestradiol an d
(b) dl-n orgestrel alon e. Th e Toxicology Review Pan el
10
of th e World Health Organ ization also assessed toxi-
cology fin din gs (World Health Organ ization 1985).
Clin ical o ve rvie w
Extent of clinical experience
Mu ch of th e in form ation regardin g th e ch aracteris-
tics of levon orgestrel im plan ts, in clu din g m ech a-
n ism s of action an d side effects, is sim ilar for Jadelle
rods an d Norplan t capsu les. Release rates an d blood
levels are com parable, as is effectiven ess over th ree
an d five years. Jadelle is easier to in sert an d rem ove
becau se it u ses two in stead of six im plan ts an d th u s
lessen s placem en t an d rem oval tim e an d tissu e trau -
m a.
Th e cu rren t Jadelle rod u n derwen t clin ical trials
begin n in g in 1990. Th e Popu lation Cou n cil con du ct-
ed stu dies com parin g Jadelle with th e earlier rod
version an d with Norplan t capsu les m ade with soft
tu bin g. Data abou t Jadelle were obtain ed from 1,393
wom en in th e followin g Cou n cil stu dies:
• ran dom ized blood level stu dies: A total of 199
wom en u sed Jadelle, h alf at fou r sites in th e
Un ited States an d h alf in Ch ile, th e Dom in ican
Repu blic, Sin gapore, an d Th ailan d. For th e first
th ree years, blood seru m con cen tration s for
wom en u sin g Jadelle were com pared with blood
levels for wom en at th e sam e sites u sin g th e earli-
er rod.
• ran dom ized Ph ase 3 clin ical trial: Th is trial com -
pared efficacy an d lon g-term effectiven ess of th e
Jadelle rods with th e soft tu bin g Norplan t cap-
su les. Six h u n dred wom en u sed Jadelle an d 594
u sed soft-tu bin g Norplan t in clin ics in Ch ile,
Egypt, Fin lan d, Sin gapore, Th ailan d, an d th e
Un ited States. Th is ran dom ized stu dy provides
data on safety an d efficacy for five years (Sivin ,
Läh teen m äki, Ran ta et al. 1997).
• com parative Ph ase 3 stu dy: Th is stu dy at five clin -
ics (fou r in th e U.S. an d on e in th e Dom in ican
Repu blic) provided safety an d efficacy data for
five years for Jadelle rods an d soft-tu bin g
Norplan t capsu les. Six h u n dred wom en u sed
each m eth od.
Contraceptive effectiveness
Th e overall assessm en t of Jadelle effectiven ess is
based on th e com parative clin ical trials described
above. Eigh t wom en becam e pregn an t du rin g th e
first five years in m u lticen ter clin ical trials with 1,393
wom en . On e of th e eigh t pregn an cies was ectopic.
Th e an n u al pregn an cy rate per 100 u sers was 0.1 at
on e, two, an d th ree years, 0.0 at fou r years, an d 0.8
at five years. Th e Pearl In dex pregn an cy rate was less
th an 0.2 pregn an cies per h u n dred wom an -years
(Sivin , Viegas, Cam podon ico et al. 1997; Sivin ,
Cam podon ico, Kiriw at et al. 1998; Popu lation
Cou n cil data su bm itted to th e FDA, 2001).
Typically, pregn an cy rates with con traceptive
m eth ods are reported on ly for th e first year of u se.
Th e efficacy of m an y of th ese m eth ods depen ds in
part on th e reliability of u se. Th is is n ot th e case for
Jadelle or Norplan t, wh ich are am on g th e m ost effec-
tive con traceptives (see Table 2). No con traceptive
m eth od is 100 percen t effective.
Relationship of weight to effectiveness
A wom an ’s weigh t correlates with blood con cen tra-
tion s of levon orgestrel: con cen tration s decrease with
in creased weigh t. Stu dies with Jadelle sh owed effec-
tive protection th rou gh five years (Sivin , Alvarez,
Mish ell et al. 1998; Sivin , Cam podon ico, Kiriwat et
al. 1998). Th rou gh fou r years, an n u al pregn an cy
rates for all wom en were less th an 0.1 per 100
wom en per year, with n o sign ifican t differen ce by
weigh t grou p. In th e fifth year, th e an n u al pregn an -
cy rate was 0.8 per 100 for all wom en . Th ere was n o
sign ifican t differen ce in th e fifth -year pregn an cy rate

Table 2. Co m p ariso n o f co n trace p tive failu re rate s d u rin g th e first ye ar o f u se

M eth od Perfect u se Typ ical u se
Jadelle rod im plan ts 0.05 0.1
Norplan t system (6 capsu les) 0.05 0.1
Male sterilization 0.10 0.15
Fem ale sterilization 0.5 0.5
Depo-Provera (in jectable progestogen ) 0.3 0.3
Oral con traceptives 5.0
Com bin ed 0.1 NA
Progestin on ly 0.5 NA
IUD
Progesteron e 1.5 2.0
Copper T 380A 0.6 0.8
Con dom
(m ale) with ou t sperm icide 3 21
(fem ale) with ou t sperm icide 5 14
Cervical cap
Nu lliparou s wom en 9 20
Parou s wom en 26 40
Spon ge
Nu lliparou s wom en 9 20
Parou s wom en 20 40
Diaph ragm with sperm icidal cream or jelly 6 18
Sperm icides alon e (foam , cream s, jellies, an d vagin al su ppositories) 6 21
Periodic abstin en ce (all m eth ods) 1–9* 20
With drawal 4 19
No con traception (plan n ed pregn an cy) 85 85
NA: Not available
*Depen din g on m eth od (calen dar, ovu lation , sym ptoth erm al, post-ovu lation )
Adapted from Hatcher, R.A. et al., Contraceptive Technology, 17th Revised Edition. New York: Ardent Media, Inc., 1998.

11
between wom en wh o weigh ed less th an 60 kg an d
wom en wh o weigh ed m ore th an 60 kg. Nor was
th ere a statistically sign ifican t differen ce in th e
cu m u lative five-year pregn an cy rates of wom en in
th ese two com preh en sive weigh t grou ps.
Outcome of pregnancies
Ectopic pregnancies: Th e absolu te risk of ectopic preg-
n an cy is low becau se th e con traceptive m eth od is
h igh ly effective. Ectopic pregn an cies occu r with
Jadelle at a rate of less th an 0.5 per 1,000 wom an -
years; th is rate is alm ost iden tical with th e ectopic
rate for Norplan t. Th is rate is sign ifican tly below th e
rate for U.S. wom en of reprodu ctive age wh o do n ot
u se con traception (2.7 to 3.0 per 1,000 wom an -
years) (Sivin 1985). It is also sign ifican tly below th e
ectopic pregn an cy rate for wom en in developin g
cou n tries wh o do n ot u se con traception (2.7 per
1,000 wom an -years), reported in postm arketin g su r-
veillan ce stu dies (Meirik, Farley, Sivin et al. 2001b).
However, an y pregn an cy th at does occu r with
Jadelle u se is m ore likely to be ectopic th an a preg-
n an cy occu rrin g in a wom an u sin g n o con tracep-
tion . Ph ysician s sh ou ld be alert to th e possibility of
an ectopic pregn an cy am on g wom en u sin g Jadelle
wh o becom e pregn an t or com plain of lower abdom -
in al pain . Clin ical an d con trolled postm arketin g
stu dies h ave sh own n o in crease in th e rate of
ectopic pregn an cies per year am on g wom en u sin g
Norplan t as com pared with wom en u sin g IUDs, con -
dom s, an d pills (Meirik, Farley, an d Sivin 2001a;
Meirik, Farley, Sivin et al. 2001b).
Birth defects: Th ere were n o reports of con gen ital
an om alies for th e pregn an cies th at occu rred du rin g
Table 3. Cu m u lative d isco n tin u atio n an d co n tin u atio n rate s fo r Jad e lle (±SE)
Reason s for d iscon tin u in g 1 3
Pregn an cy 0.1±0.1
Men stru al 4.5±0.6
Medical 4.7±0.6
Used oth er m eth od 0.2±0.1
Plan n ed pregn an cy 1.1±0.3
Person al (oth er) 1.6±0.3
Con tin u ation 88.3±0.9
12
u se of Jadelle in clin ical trials. However, in postm ar-
ketin g u se of Norplan t, th ere h ave been reports of
con gen ital an om alies in th e offsprin g of wom en wh o
were u sin g th e con traceptive in adverten tly du rin g
early pregn an cy. A cau se an d effect relation sh ip h as
n ot been establish ed. Th ere is n o eviden ce su ggestin g
th at th e risks associated with levon orgestrel-con tain -
in g im plan ts are differen t from th ose associated with
oral con traceptives.
In th e WHO–Popu lation Cou n cil–FHI five-year
postm arketin g su rveillan ce of Norplan t im plan ts,
reported birth an om alies were of th e sam e kin d an d
frequ en cy as th ose reported for a larger grou p of
wom en from th e sam e stu dy wh o con ceived after
u sin g IUDs or oth er n on h orm on al m eth ods (Meirik,
Farley, an d Sivin 2001a; Meirik, Farley, Sivin , et al.
2001b).
Exten sive epidem iological stu dies h ave revealed
n o in creased risk of birth defects in wom en wh o h ave
u sed oral con traceptives before pregn an cy. Stu dies
also do n ot su ggest a teratogen ic effect, particu larly
in sofar as cardiac an om alies an d lim b-redu ction
defects are con cern ed, wh en oral con traceptives are
taken in adverten tly du rin g early pregn an cy.
Continuation and termination rates
In th e Jadelle clin ical trials, th e first-year con tin u a-
tion rate was 88.3 per 100 wom en , th e th ree-year
cu m u lative rate was 60.6 per 100, an d th e five-year
cu m u lative rate was 41.5 per 100 (see Table 3). In
th e first year, 4.5 per 100 wom en cited irregu lar
bleedin g as th e prin cipal reason for discon tin u in g th e
m eth od. Th e cu m u lative rate for discon tin u ation
becau se of irregu lar bleedin g was 14.1 per 100
Year
5
0.3±0.2 1.1±0.4
14.1±1.0 19.3±1.2
14.7±1.0 23.1±1.3
0.9±0.3 3.7±0.7
9.7±0.9 18.6±0.3
7.2±0.8 12.5±0.1
60.6±1.3 41.5±1.3
th rou gh th e th ird year an d 19.3 per 100 th rou gh th e
fifth year. Oth er m edical con dition s were cited as Table 4. Me n stru al co n d itio n s re p o rte d in
reason s for stoppin g m eth od u se by 4.7 per 100 u sers clin ical trials o f Jad e lle
in th e first year, 14.7 per 100 cu m u latively by th e M en stru al con d ition Year 1 (% ) Years 1–5 (% )
th ird year, an d 23.1 per 100 cu m u latively by th e fifth
Men orrh agia
year. Th ree con dition s—h eadach e, weigh t gain , an d (in creased du ration ) 13.4 25.9
acn e—join tly accou n ted for m ore th an 50 percen t of Am en orrh ea 9.8 13.9
th e m edical rem ovals. Abou t 10 percen t of th e Men om etrorrh agia 9.6 20.5
wom en stopped u se before th e en d of th e th ird year Oligom en orrh ea 9.5 12.8
an d abou t 19 percen t by th e en d of th e fifth year Lon g spottin g du ration or
becau se th ey desired to becom e pregn an t (Sivin , len gth u n clear 8.9 15.1
Cam podon ico, Kiriwat et al. 1998). Dysm en orrh ea 3.5 a 8.0 a
Polym en orrh ea 2.7 5.0
Possible adverse events
Prem en stru al syn drom e 1.8 a 5.8 a
Clin ical trial in vestigators record all m edical con di-
Men orrh agia
tion s an d com plain ts reported by th e participan ts
(in creased am ou n t) 1.6 4.5
du rin g m eth od u se, wh eth er or n ot th ese con dition s
Oth er 1.5 2.9
are th ou gh t to be directly related to th e m eth od.
a Exclu des wom en with con dition s reported at
Possible side effects and adverse events listed here
adm ission , before in itiation of Jadelle
were reported during Jadelle clinical trials.
Bleeding irregularities: Becau se Jadelle con tain s
n o estrogen , disru ption of th e m en stru al cycle is th e can n ot serve as th e on ly m ean s of iden tifyin g early
m eth od’s predom in an t side effect. Most wom en can pregn an cy. Pregn an cy tests sh ou ld be perform ed
expect som e variation in m en stru al bleedin g pat- wh en ever a pregn an cy is su spected. Six weeks or
tern s. Wom en u sin g Jadelle can expect th e sam e m ore of am en orrh ea after a pattern of regu lar
irregu larities as do Norplan t u sers: irregu lar m en - m en ses m ay sign al pregn an cy. If pregn an cy occu rs,
stru al bleedin g, prolon ged episodes of bleedin g or th e rods m u st be rem oved.
spottin g (m ore days th an a wom an wou ld u su ally Alth ou gh w om en in clin ical trials reported
experien ce), h eavy bleedin g, bleedin g or spottin g bleedin g irregu larities, proportion ately m ore wom en
between periods, n o bleedin g at all for several h ad in creases rath er th an decreases in blood h em o-
m on th s, or a com bin ation of th ese pattern s (Balogh , globin con cen tration s, a differen ce th at was h igh ly
Klavon , Basn ayake et al. 1989; Bisw as, Leon g, statistically sign ifican t (Sivin 1988). Th is fin din g gen -
Ratn am et al. 1996; Diaz, Pavez, Herreros et al. 1986; erally in dicates th at, despite in creased bleedin g days,
Fakeye an d Balogh 1989; Fau n des, Dem ejias, Leon m en stru al blood loss was redu ced for Jadelle u sers.
et al. 1979; Fau n des, Tejada, Brach e et al. 1987; Sivin Sim ilar resu lts were reported with Norplan t capsu les
1988; Sivin , Viegas, Cam podon ico et al. 1997) (see (Fau n des, Tejada, Brach e et al. 1987; Gu , Du , Yu an
Table 4). No on e can predict wh at kin d of m en stru al et al. 1988; Sh aaban , Salah , Zarzou r et al. 1983).
ch an ge a wom an will h ave with Jadelle. Bu t, for Rarely, blood loss resu lted in h em oglobin valu es
m ost wom en , th ese m en stru al irregu larities will in dicative of an em ia.
dim in ish gradu ally with con tin u in g u se (Biswas, Other adverse events: Aside from menstrual irregu-
Leon g, Ratn am et al. 1996). Altered bleedin g pat- larities, adverse reactions reported by more than 10
tern s associated with Jadelle u se cou ld possibly m ask percent of women in the Jadelle clinical trials were
sym ptom s of cervical or en dom etrial can cer, pain, discoloration or other skin reactions at the
alth ou gh th is was n ot observed in an y of th e stu dies implant site, dizziness, headache, leukorrhea, mastal-
of Jadelle or Norplan t. gia, nausea, pelvic pain, urinary tract symptoms/infec-
Becau se som e levon orgestrel im plan t u sers h ave tion, vaginitis, and weight increase. All but pain and
periods of am en orrh ea, m issed m en stru al periods discoloration or other skin reactions at the implant site

13
are adverse reactions common to other hormonal
con traceptives. Table 5 sh ow s adverse reaction s
reported during Jadelle clinical trials.
Ovarian cysts
Ovarian cysts or delayed follicu lar atresia som etim es
occu rred in Jadelle u sers. If follicu lar developm en t
occu rs, atresia of th e follicle m ay be delayed an d th e
follicle m ay con tin u e to grow beyon d th e size it
wou ld attain in a n orm al cycle. Th e cysts are gen er-
ally asym ptom atic bu t m ay be palpable by clin ician s;
in th e m ajority of wom en , th e en larged follicles
(cysts) will u su ally disappear spon tan eou sly after a
few weeks an d do n ot requ ire su rgery. Rarely, th ey
m ay twist or ru ptu re, som etim es cau sin g abdom in al
pain an d su rgical in terven tion m ay be requ ired. In

Table 5. A d ve rse re actio n s d u rin g five ye ars o f Jad e lle u se in clin ical trials

Ad verse reaction s rep orted b y 10% or m ore of w om en :

Application site reaction , pain , etc. Nau sea
Dizzin ess Pelvic pain
Headach e Urin ary tract sym ptom s, in fection
Leu korrh ea Vagin itisa
Mastalgia Weigh t in crease
a
in clu des also gen ital pru ritu s, in fection s, an d vagin al problem s n ot elsewh ere classified

Ad verse reaction s rep orted b y 1.0 to 9.9% of w om en :

Abdom in al pain Follicu litis
Abn orm al vision Hyperten sion
Acn e Hypertrich osis
Alopecia Hypoesth esia
An orexia In ju ry
An xiety In som n ia
Appetite in crease Libido decreased
Asth en ia Migrain e
Asth m a Nervou sn ess
Back pain Non pu erperal lactation
Ben ign breast n eoplasm Ovarian cyst, follicle en largem en t
Breast fibroaden osis Pain
Bron ch itis Palpitation
Cervical cytology, grade 3 or 4 Perin eal pain
Cervical lesion Pru ritu s
Cervicitis Pu rpu ra
Ch est pain Rash
Con stipation , flatu len ce, or dyspepsia Som n olen ce
Con tact derm atitis Syn cope
Depression Upper respiratory in fection b
Derm atitis Uterin e en largem en t
Dyspareu n ia Varicose vein s
Dyspn ea Vom itin g
Em otion al lability Vu lvar disorder c
Fatigu e Weigh t decrease
Flu -like sym ptom s
b
in clu des rh in itis, ph aryn gitis, an d sin u sitis, as well as u n defin ed u pper respiratory in fection
c
in clu des gen ital u lceration , h erpes sim plex, an d papillom a viru s an d oth er vu lvar disorders

14
th e Popu lation Cou n cil’s clin ical trials, su rgery for
delayed follicu lar atresia was perform ed in fou r of
1,400 wom en over seven years.
Weight gain
In clin ical trials of Jadelle u se, th e average weigh t
ch an ge over five years of u se was a gain of abou t 9
pou n ds. Approxim ately 20 percen t of wom en gain ed
at least 10 pou n ds in th e first year, an d 50 percen t
gain ed at least 10 pou n ds by th e en d of th e fifth year
of u se.
Insertion and removal
Jadelle rods can be in serted ju st below th e skin of th e
wom an ’s in n er u pper arm th rou gh a sm all in cision
m ade eith er with a scalpel or a disposable pre-loaded
in serter. Th e two rods are placed in th e sh ape of a V
open in g toward th e sh ou lder. Strict asepsis m u st be
observed to avoid in fection . Train in g of h ealth care
providers is essen tial for proper placem en t an d
rem oval. Th e better th e placem en t, th e easier
rem oval will be.
Rem oval tim es were recorded for 260 Jadelle
an d 260 Norplan t u sers. From in cision to closu re,
m ean rem oval tim e for Jadelle was 4.8 m in u tes,
wh ile rem ovals in th e Norplan t grou p took 9.6 m in -
u tes. Am on g th e rod rem ovals, 2 percen t requ ired
m ore th an 15 m in u tes, wh ile 14 percen t of Norplan t
rem ovals n eeded th at tim e an d 6.5 percen t took
lon ger th an 20 m in u tes. Mean rod rem oval tim es
ran ged from 4.6 to 5 m in u tes, com pared with 7.8 to
10.9 m in u tes for Norplan t rem oval (Sivin ,
Cam podon ico, Kiriwat et al. 1998).
Insertion complications: An in cision is requ ired to
in sert Jadelle im plan ts. Com plication s related to
in sertion , su ch as pain , edem a, an d bru isin g, m ay
occu r. Bru isin g is com m on ly seen followin g im plan t
placem en t. Arm pain , n u m bn ess, an d tin glin g m ay
occu r followin g in sertion an d rem oval. Reports of
in fection (in clu din g cellu litis an d abscess form ation ),
blisterin g, u lceration s, slou gh in g, excessive scarrin g,
ph lebitis, an d h yperpigm en tation h ave been report-
ed at th e in sertion site for Norplan t an d m ay occu r
with Jadelle. Reports of n erve in ju ry, m ost com m on -
ly associated with deep placem en t an d rem oval, also
were reported with Norplan t.
Du rin g Jadelle clin ical trials, in fection at th e
in sertion site occu rred in 0.4 percen t of wom en over
five years. Expu lsion of on e or both rods, wh ich was
u n com m on du rin g th e trials, is m ore likely to occu r
wh en placem en t of th e rods is extrem ely sh allow,
too close to th e in cision , or wh en th e area is in fect-
ed. Th ere h ave been reports of im plan t m ovem en t,
m ost of wh ich in volved m in or ch an ges in position of
th e im plan ts, bu t som e h ave in volved sign ifican t dis-
placem en t of u p to several in ch es.
Removal complications: Rem oval is ach ieved
th rou gh an in cision close to th e rods. Rem oval m ay
take lon ger, be m ore difficu lt, an d/ or cau se m ore
pain th an in sertion an d m ay be associated with diffi-
cu lty in locatin g im plan ts. Addition al in cision s
an d/ or office visits m ay be requ ired. Th e two-rod
system is expected to redu ce th e in ciden ce of
rem oval difficu lties in com parison with Norplan t.
In a five-year stu dy of th e perform an ce of levo-
n orgestrel rods an d im plan ts, 52 (9.9 percen t) of 524
rem ovals were con sidered to h ave com plication s.
Rem ovals produ ced som e com plication in 6.9 per-
cen t of rod u sers an d 14.8 percen t of Norplan t u sers.
Half of th e Norplan t com plication s were reported at
a sin gle clin ic (Sivin , Cam podon ico, Kiriwat et al.
1998). Man y of th ese difficu lties were related to
im proper placem en t. In all of th e Popu lation
Cou n cil’s clin ical trials of Jadelle, rem oval problem s
affected 1.5 percen t of u sers (deep placem en t, m u lti-
ple or lon g in cision s, bru isin g, displacem en t, or
pain ), wh ile an addition al 6.0 percen t in volved prob-
lem s for providers (broken im plan ts an d fibrou s peri-
capsu lar tissu e).
Reversibility/return to fertility
Rates an d ou tcom es of plan n ed pregn an cy were
stu died am on g u sers of fou r lon g-actin g con tracep-
tives: an earlier version of th e rods, Norplan t cap-
su les, an d two in trau terin e devices (Sivin , Stern ,
Diaz et al. 1992). Th is stu dy fou n d th at 83 per 100
Norplan t u sers an d 84 per 100 rod u sers becam e
pregn an t by th e en d of th e first year after stoppin g
con traception , wh ile 87 per 100 Norplan t u sers an d
92 per 100 rod u sers becam e pregn an t by th e en d of
two years. An oth er stu dy of 214 Jadelle u sers
sh owed th at 42 percen t becam e pregn an t at th ree
m on th s, 86 percen t at on e year, an d 92 percen t by
two years (Sivin , person al com m u n ication , 2001).
Addition al eviden ce th at prolon ged u se of
Norplan t capsu les does n ot im pair su bsequ en t fecu n -
15
dity was provided in a stu dy in In don esia, wh ere
post-rem oval con ception rates for form er Norplan t
u sers are reported to be virtu ally iden tical with th ose
of form er IUD an d in jectable con traceptive u sers
(Affan di, San toso, Djajadilaga et al. 1987a).
Effect on lactation
Steroids are n ot con sidered th e con traceptives of first
ch oice for breastfeedin g w om en (Win ikoff,
Sem eraro, an d Zim m erm an 1988). Levon orgestrel is
tran sferred from m atern al circu lation to th e n ew-
born in fan t’s circu lation via breastm ilk (Sh aaban ,
Odlin d, Salem et al. 1986; Sh ikary, Betrabet, Patel et
al. 1987). However, stu dies h ave revealed n o clin i-
cally im portan t effects on th e growth or h ealth of
in fan ts wh ose m oth ers u se levon orgestrel im plan ts
begin n in g six weeks after ch ildbirth (Diaz 1998;
Diaz, Herreros, Ju ez et al. 1984, 1985). A com pre-
h en sive stu dy of in fan t developm en t an d progesto-
gen -on ly con traceptives in five cou n tries fou n d n o
adverse effect on developm en t of in fan ts wh ose
m oth ers u sed progestogen -on ly m eth ods com pared
with in fan ts wh ose m oth ers u sed n on h orm on al
m eth ods du rin g breastfeedin g (World Health
Organ ization 1994).
Drug interactions
Jadelle is n ot recom m en ded for wom en with epilep-
sy wh o u se ph en ytoin , carbam azepin e, or oxcar-
bazepin e, becau se Jadelle is likely to be less effective
for th ese wom en . Th ese dru gs m ay in crease th e
m etabolism of levon orgestrel th rou gh in du ction of
m icrosom al liver en zym es. Alth ou gh th e large clin i-
cal trials of Norplan t an d Jadelle exclu ded wom en
with epilepsy, pu blish ed stu dies sh ow decreased
levon orgestrel con cen tration s in w om en u sin g
ph en ytoin , carbam ezepin e, or oxcarbazepin e alon g
w ith levon orgestrel-con tain in g con traceptives
(Hau kkam aa 1986; Odlin d an d Olsson 1986). In
clin ical trials of Norplan t, rifam pin was ju dged to
h ave dim in ish ed th e effectiven ess of th e con tracep-
tive as it does with oth er progestin -on ly produ cts
(Un ited States Ph arm acopeia 1999).
Me tabo lic e ffe cts
Ju dgm en ts on m etabolic effects derive from exten -
sive stu dies of ph arm acologic in dicators am on g u sers
16
of levon orgestrel im plan ts, in clu din g Jadelle, an ear-
lier rod version , an d Norplan t capsu les.
In dicators of ch an ge in liver an d kidn ey fu n ction
an d in m etabolism in wom en u sin g Norplan t h ave
been m on itored in several stu dies (Affan di,
Su h erm an , Djajalelan a et al. 1987; Bayad, Ibrah im ,
Fayad et al. 1983; Brach e, Alvarez-San ch ez, Fau n des
et al. 1990; Croxatto, Diaz, an d Pavez 1978;
Croxatto, Diaz, Robertson et al. 1983; Dash , Das,
Nan da et al. 1988; Diaz, Pavez, Bran deis et al. 1989;
Diaz, Pavez, Robertson et al. 1979; Holm a an d
Robertson 1985; Joh an sson an d Odlin d 1983; Nash
1990; Olsson , Wide, an d Odlin d 1986; Osm an ,
Abdalla, Toppozada et al. 1983; Sh aaban , Elwan , El-
Sh arkawy et al. 1984; Sin gh , Viegas, Koh et al.
1989a, 1989b, 1989c; Wein er an d Joh an sson 1976).
Th ey are su m m arized below.
Liver function
Assessm en t is based on total biliru bin , direct biliru -
bin , total protein , albu m in , alkalin e ph osph atase,
lactic deh ydrogen ase, SGOT, SGPT, an d GGT. Th e
on ly con sisten t ch an ge h as been a sm all in crease in
total biliru bin , with all m ean s rem ain in g with in th e
n orm al ran ge. Th e ch an ge h as been n on -progressive
over exten ded periods of im plan t u se.
Kidney function
Assessm en t is based on levels of u ric acid, u rea n itro-
gen , sodiu m potassiu m , calciu m , an d in organ ic
ph osph orou s. Th ere were n o in dication s of com pro-
m ised kidn ey fu n ction .
Adrenal function
Eith er n o ch an ge or a sligh t decrease in periph eral
cortisol levels was reported, bu t with in n orm al
ran ge. Respon se to ACTH stim u lation was n orm al.
Thyroid function
Som e eviden ce was reported of m in or decrease in
th yroxin an d triiodoth yron in e levels, n ot accom pa-
n ied by ch an ges in free th yroxin .
Lipid metabolism
Seru m lipoprotein levels were altered in th ree clin i-
cal stu dies in volvin g 544 wom en u sin g Jadelle. Th e
rod u sers h ad m ean decreases from baselin e in total
ch olesterol, h igh -den sity lipoprotein (HDL) ch oles-
terol, an d low-den sity lipoprotein (LDL) ch olesterol
of approxim ately 12 percen t, 14 percen t, an d 10 per-
cen t respectively. Triglyceride levels decreased abou t
25 percen t from pretreatm en t valu es. Alth ou gh
th ese decreases were statistically sign ifican t, a great
m ajority of in dividu al valu es rem ain ed with in th e
n orm al ran ges. Ch an ges in th e lipoprotein levels
associated with levon orgestrel im plan ts are con sid-
ered to h ave little, if an y, deleteriou s effect on th e
risk of cardiovascu lar disease.
A two-year lon gitu din al stu dy u n dertaken by
th e WHO com pared 177 Norplan t u sers with a sim i-
lar n u m ber of copper IUD u sers. Th e stu dy fou n d
ch an ges of sim ilar m agn itu de to th ose cited above.
Lipid ch an ges were greatest th ree m on th s after
im plan t in sertion , with a slow reversal of th ese
tren ds du rin g th e n ext 19 m on th s. Th e report con -
clu des th at lipid ch an ges in du ced by Norplan t
will probably n ot affect th e risk of ath erosclerotic dis-
ease in wom en wh o u se th is con traceptive m eth od
(WHO 1999).
Wom en w h o are bein g treated for h yperlipi-
dem ias sh ou ld be follow ed closely if th ey elect to
u se Jadelle. Som e progestin s m ay elevate LDL lev-
els an d m ay ren der th e con trol of h yperlipidem ias
m ore difficu lt.
Carbohydrate metabolism
Decreased in su lin sen sitivity followin g glu cose load-
in g h as been fou n d in som e u sers of com bin ation
an d progestin -on ly oral con traceptives. Th e effect of
levon orgestrel-con tain in g im plan ts on carboh ydrate
m etabolism appears to be m in im al. In stu dies in
wh ich pretreatm en t fastin g seru m glu cose con cen -
tration s were com pared with con cen tration s follow-
in g u p to 20 m on th s of Jadelle u se, n o clin ically sig-
n ifican t m ean differen ces were eviden t. Ch an ges in
carboh ydrate toleran ce an d in su lin sen sitivity fol-
lowin g oral glu cose loads h ave been reported in
som e stu dies am on g u sers of Norplan t capsu les an d
Jadelle rods (Sin gh , Viegas, Loke et al. 1992; Bala,
Dh all, an d Maju m dar 1991; Kon je, Otolorin , an d
Ladipo 1991; Kon je, Odu koya, Otolorin et al. 1992;
Kon je, Otolorin , an d Ladipo 1992). Th ese ch an ges
in clu de m odest elevation s of seru m in su lin con cen -
tration s as well as in crem en ts in seru m glu cose lev-
els. Th ese ch an ges were n ot associated with develop-
m en t of clin ical or laboratory eviden ce of diabetes
m ellitu s. Wh ile th e clin ical sign ifican ce of th ese fin d-
in gs is u n kn own , diabetic patien ts sh ou ld be carefu l-
ly observed wh ile u sin g Jadelle. Du rin g th e Norplan t
postm arketin g su rveillan ce stu dy, diabetes m ellitu s
developed in Norplan t u sers at th e rate of 0.2 per
1,000 wom an -years, a rate n ot sign ifican tly above
th at of wom en wh o were u sin g IUDs or sterilization
(Meirik, Farley, an d Sivin 2001a; Meirik, Farley,
Sivin et al. 2001c).
Hematology
In gen eral, th ere h ave been n o n oteworth y fin din gs
in blood cell cou n ts am on g Jadelle u sers. An excep-
tion is platelet cou n ts, wh ich were fou n d to in crease
in stu dies in Sin gapore (Sin gh , Viegas, Loke et al.
1993b), as did in dicators of platelet aggregation ten -
den cy. However, in stu dies in th ree oth er clin ics,
platelet cou n ts decreased du rin g im plan t u se (Gu ,
Du , Zh an g et al. 1993). Stu dies of coagu lation fac-
tors, coagu lation in h ibitors, an d fibrin olytic in dica-
tors in Sin gapore (Sin gh , Viegas, Loke et al. 1992)
eviden ced sm all decreases in proth rom bin tim e an d
activated partial th rom boplastin tim e, decreases in
several coagu lation prom otion factors (II, V, VII), an d
n o ch an ge in fibrin olytic activity or coagu lation
in h ibitors.
Hemoglobin
Despite ch an ges in m en stru al bleedin g pattern s,
m ean h em oglobin levels am on g Jadelle u sers
rem ain ed u n ch an ged or in creased. Experien ce
am on g Norplan t u sers h as sh own th at in rare cases,
m en stru al bleedin g is su fficien tly volu m in ou s to
decrease h em oglobin con cen tration m arkedly.
Endocrine changes
Estradiol seru m levels du rin g Norplan t u se h ave
sh own irregu lar pattern s, with base valu es of 30–70
picogram s per m illiliter an d occasion al peaks reach -
in g between 200 an d 400 picogram s per m illiliter or,
in frequ en tly, peaks of approxim ately 600 picogram s
per m illiliter. Average estradiol levels can vary great-
ly, ran gin g from a low of abou t 50 picogram s per m il-
liliter du rin g m en ses an d th e first week or so of th e
follicu lar ph ase to a h igh of abou t 200 picogram s per
m illiliter after th e LH peak. Peaks can be m u ch h igh -
er th an th ese n orm s or averages.
Statistically sign ifican t decreases in circu latin g
total testosteron e an d an drosten edion e h ave been
17
fou n d am on g levon orgestrel im plan t u sers. Th ey
were accom pan ied by large decreases in sex h or-
m on e bin din g globu lin (SHBG). Sin ce testosteron e is
h igh ly bou n d to SHBG, th e decreased SHBG con cen -
tration s predict sligh tly lower testosteron e con cen -
tration s. Un bou n d testosteron e con cen tration s were
essen tially u n ch an ged. Th ese stu dies give n o evi-
den ce th at th e effect of Jadelle u se on an drogen s is
likely to be of clin ical sign ifican ce.
Several path ologists h ave evalu ated th e effect of
th e altered h orm on e pattern s on th e en dom etriu m .
Som e 150 en dom etrial biopsies from wom en wh o
u sed Norplan t for 2 to 116 m on th s were exam in ed
h istologically. Th e pictu re is on e of m ixed prolifera-
tive an d secretory activity, with a fairly large n u m ber
of biopsies sh ow in g con siderable su ppression .
Accordin g to path ologists, h istological stu dies h ave
iden tified n o cau se for clin ical con cern . Of som e 150
biopsies for wh ich h istological in terpretation is avail-
able, on ly two sh owed h yperplastic ch aracteristics
an d an oth er two som e degree of decidu alization .
Several in vestigators wh o exam in ed th e effect of
du ration of im plan t u se on en dom etrial pattern s
h ave fou n d n o con vin cin g eviden ce of progressive
ch an ges in pattern with len gth of u se.
18
Su m m in g u p
In 1998, th e In stitu te of Medicin e pu blish ed a
report based on a w orksh op, Contraceptive Research,
Introduction, and Use: Lessons from Norplant (In stitu te
of Medicin e 1998). Th e report con clu ded th at “both
Norplan t an d th e tw o-rod levon orgestrel im plan t
system are h igh ly efficaciou s w ith failu re rates
u n der 1 percen t per year, th u s providin g reversible
con traceptive protection essen tially equ al to th at of
perm an en t m eth ods, th at is, tu bal ligation an d
vasectom y.”
With respect to safety, th e report said th at “As
w ith all h orm on al m eth ods, th e con traceptive
im plan t is u n su itable for som e wom en an d th ose
con train dication s are detailed in its labelin g. Th e
Postm arketin g Su rveillan ce an d Popu lation Cou n cil
stu dies fou n d seriou s adverse even ts to be extrem ely
rare am on g im plan t u sers over five years of stu dy
an d con clu ded th at, in th e settin gs wh ere th ose stu d-
ies were carried ou t, th e m eth od proved to be safe
an d well-tolerated.”
“In su m ,” th e report con tin u ed, “n o good scien -
tific reason s em erged in th e worksh op for n ot m ak-
in g Norplan t available to all wom en for wh om its u se
is n ot cou n terin dicated in labelin g.”
RECOMMEN D ATION S FOR IN TROD UCIN G
JA D ELLE IN TO D EVELOPIN G-COUN TRY
FA MILY PLA N N IN G PROGRA MS: LESSON S
LEA RN ED FROM THE N ORPLA N T EXPERIEN CE
Fam ily plan n in g profession als an d policym akers can
learn from th e Norplan t experien ce—in th eir own
cou n tries or in oth ers—wh eth er, or h ow best, to
in trodu ce or in corporate Jadelle im plan ts in to exist-
in g fam ily plan n in g program s. In addition , th e
Popu lation Cou n cil in collaboration with local part-
n ers in th e Dom in ican Repu blic an d Gu atem ala in i-
tiated tran sition stu dies on h ow program s th at cu r-
ren tly provide Norplan t can su ccessfu lly offer
Jadelle, eith er as an addition al or replacem en t
im plan t option . (For details on th ese tran sition stu d-
ies, see th e first section of th is m on ograph .)
Th e recom m en dation s listed below, wh ile specif-
ic to im plan ts, raise som e gen eral poin ts th at cou ld
be applied as well to h igh -qu ality provision of oth er
lon g-actin g, provider-depen den t con traceptives.
Th ese recom m en dation s are n ot absolu tes—som e
program s m ay h ave difficu lty ach ievin g all of th em —
bu t th ey are gu idin g prin ciples th at Popu lation
Cou n cil h ealth profession als wh o are experien ced in
provision of Norplan t believe are worth con siderin g.
A discu ssion of som e of th ese issu es also can be
fou n d in Contraceptive Research, Introduction, and Use:
Lessons from Norplant (In stitu te of Medicin e 1998).
Establish in g stan dardized practices to ach ieve an
acceptable level of qu ality of care, in clu din g tech n i-
cal com peten ce an d cou n selin g, sh ou ld be part of th e
plan n in g for th e in trodu ction of im plan ts.
Un derstan din g th e differen t types of service delivery
system s—com m ercial, pu blic, private, n on govern -
m en tal organ ization (NGO)—in wh ich th e m eth od
m ay be offered is essen tial. In settin gs wh ere a large
popu lation is at risk for sexu ally tran sm itted dis-
eases, atten tion sh ou ld be paid to th e appropriate-
n ess of su ch a m eth od given th at im plan ts will n ot
protect again st STDs.
When considering Jadelle, family planning pro-
gram managers should be aware that implants will fill
a small niche in their cafeteria of choices and that no
one contraceptive method should be touted as a
panacea for solving demographic and social problems.
We offer th ese recom m en dation s, based on th e
experien ce of pu blic h ealth experts from th e
Popu lation Cou n cil an d cou n try an d in tern ation al
organ ization s:
1. Program assessment should precede
Jadelle introduction
Before a cou n try in corporates Jadelle in to its n ation -
al fam ily plan n in g program , it sh ou ld u n dertake an
assessm en t of th e capacity of its services to deliver
th e m eth od in a safe m an n er. If th e program h as past
or cu rren t experien ce with Norplan t im plan ts, a
review of th at experien ce sh ou ld poin t ou t stren gth s
or weakn esses of im plan t provision . Addition of
Jadelle m ay provide an opportu n ity to im prove
im plan t delivery an d th e qu ality of services an d to
attract n ew u sers.
Jadelle rods, like Norplant capsules, have a num-
ber of characteristics that may make them appropriate
in some settings. Implant technology should not auto-
matically be introduced in every setting: some family
planning programs can manage the method well,
while others do not have the requisite infrastructure.
The provision of this method requires that there be:
• atten tion to cou n selin g an d in form ation provided
to clien ts;
• access to an d availability of train ed providers at
th e tim e of in sertion an d w h en rem oval is
requ ested an d/ or n eeded;
• assu ran ce of provider com peten ce;
• adh eren ce to aseptic procedu res at all tim es;
• a well-fu n ction in g logistics system to m ain tain th e
delivery of com m odities an d all related equ ip-
m en t;
• a relatively soph isticated m an agem en t in form a-
tion system (MIS) to locate clien ts at th e en d of
th e period for wh ich th e m eth od is approved;
• su pervision an d evalu ation system s to m on itor
qu ality of care;
• su stain ed com m itm en t by n ation al program s or
don ors to provide Jadelle;
19
• private location for in sertion s an d rem ovals an d
con fiden tial cou n selin g.
2. Addition of Jadelle should expand contraceptive
choice
Jadelle sh ou ld be offered with in th e con text of a
ran ge of m eth ods in order to in crease option s avail-
able for wom en . Jadelle sh ou ld be position ed as a
lon g-actin g altern ative to sh ort-term con traceptives,
su ch as birth con trol pills, or as a su bstitu te for ster-
ilization , th e IUD, or in jectables. With in m an y set-
tin gs, im plan ts can h ave an im portan t place in a pro-
gram ’s m eth od m ix. However, if Jadelle is n ot wide-
ly available or if its provision can n ot be su stain ed
over tim e (becau se of cost or train in g requ irem en ts
or for an y oth er reason ), th en its addition will n ot
au tom atically expan d ch oice. Th e WHO h as devel-
oped a strategic approach th at in clu des an assess-
m en t of th e n eed for a n ew con traceptive in an exist-
in g n ation al fam ily plan n in g program (WHO 1996).
3. Community participation should be part of an intro-
duction strategy
Key stakeh olders—m in istry of h ealth officials, NGO
program m an agers, service providers, w om en ’s
h ealth advocates, an d poten tial u sers—sh ou ld be
in clu ded, to th e exten t possible, in th e design an d
im plem en tation of an in trodu ction strategy. Failu re
to in volve th e com m u n ity in in trodu ction efforts
can h ave a n egative effect on th e perform an ce an d
acceptability of th e m eth od an d th e fam ily plan n in g
program m ore gen erally, particu larly if m isin form a-
tion an d ru m ors are n ot corrected. In terested stake-
h olders sh ou ld be provided w ith u n derstan dable
in form ation abou t issu es related to proper u se,
in clu din g th e m eth od’s safety, efficacy, poten tial
side effects, retu rn to fertility, an d th e lack of pro-
tection again st disease. A fu ll discu ssion w ith com -
m u n ity grou ps sh ou ld precede th e in trodu ction of
Jadelle.
4. Jadelle rods should be acceptable to clients who
choose to use them
Nu m erou s stu dies of both rods an d capsu les h ave
docu m en ted th eir safety an d efficacy. However, safe-
ty an d efficacy do n ot n ecessarily tran slate in to social
or cu ltu ral acceptability. For exam ple, th e irregu lar
bleedin g th at resu lts from a progestin -on ly m eth od
20
m ay cau se problem s for wom en . In som e societies,
wom en m ay wan t th eir h u sban ds to be in form ed
abou t th e m eth od; in oth er settin gs, wom en m igh t
n ot wan t to in volve th eir spou ses. Clien ts also sh ou ld
kn ow th at Jadelle, like oth er h orm on al con tracep-
tives, offers n o protection again st HIV/ AIDS an d
oth er STDs.
5. The method should be sustainable once it is introduced
Becau se Jadelle in itially h as greater u p-fron t costs
th an oth er m eth ods, th e in trodu ction strategy
sh ou ld en su re an adequ ate su pply of im plan ts over
tim e, th rou gh don or pu rch ases, cou n try con tribu -
tion s, an d, w h ere possible, th e private sector.
However, lon g-ran ge prediction s of wh at con stitu tes
an adequ ate su pply m ay n ot be attain able at th e ou t-
set of program plan n in g; th e system n eeds to h ave
room for feedback.
6. Jadelle providers must be trained in insertion and
removal techniques
Ph ysician s, n u rse-m idwives, an d param edics can
provide Jadelle, as lon g as th ey h ave been well
train ed in in sertion s an d rem ovals an d h ave appro-
priate equ ipm en t an d su pplies. In addition , sin ce
providers often are called u pon to rem ove im plan ts
lon g after in itial train in g, retrain in g in rem oval tech -
n iqu es is often essen tial. In large part, th e ease in
rem ovin g Jadelle relates to h ow well th e rods were
in serted. Rem ovin g (an d in sertin g) Jadelle is expect-
ed to be easier th an in th e case of Norplan t, becau se
th ere are on ly two rods com pared with six capsu les.
In a large stu dy, m ean rem oval tim e for th e rods was
reported as 4.8 m in u tes, wh ile m ean rem oval tim e
for Norplan t capsu les was 9.6 m in u tes. Program s
sh ou ld en su re th at su fficien t n u m bers of providers
are train ed in in sertion an d rem oval tech n iqu es to
h an dle th e expected case load, particu larly wh en
th ere will be large n u m bers of wom en seekin g
rem oval at th e en d of Jadelle’s approved u se life.
7. Clinic staff should be trained in counseling tech-
niques and concepts
Sen sitive an d com preh en sive cou n selin g abou t all
available con traceptives—n ot on ly Jadelle—w ill
en able a wom an to decide wh ich m eth od is best for
h er. Cou n selin g sh ou ld in clu de in form ation abou t all
m eth ods available at th e service delivery poin t, alon g
with in form ation con cern in g th e degree to wh ich
th ey offer protection again st sexu ally tran sm itted
diseases. Cou n selin g sh ou ld be in tegrated in to on go-
in g train in g an d su pervisory tasks. Ph ysician s an d
oth er clin ic staff h ave ben efited from bein g in clu ded
in cou n selin g worksh ops. Cou n selin g abou t m en -
stru al bleedin g irregu larities related to im plan ts an d
oth er progestin -on ly con traceptive m eth ods is th e
best way to m in im ize discon tin u ation for th is reason .
8. Accurate information should be prepared for clients,
providers, and the community
In form ation al m aterial for clien ts an d service
providers m u st be developed an d produ ced in appro-
priate lan gu ages, particu larly if im plan ts h ave n ot
been available previou sly. Wom en an d clin ician s
n eed to kn ow h ow im plan ts com pare with oth er
con traceptives; th at th ey do n ot protect again st STDs;
abou t side effects an d possible com plication s; abou t
th e in sertion an d rem oval procedu res; an d abou t
access to tim ely rem oval. If Jadelle will be provided
in addition to or in stead of Norplan t im plan ts, th e
m ost salien t tech n ical differen ces an d sim ilarities
between th e two im plan t system s m u st be com m u -
n icated to program m an agers an d providers.
9. Supervision and ongoing program evaluation are
essential
A strategic in trodu ction plan sh ou ld en su re th e
appropriate su pervision of providers. In addition ,
program s n eed a clien t trackin g system or oth er
m eth ods, su ch as pu blication s or correspon den ce, to
en su re th at wom en retu rn for Jadelle rem oval at th e
en d of th e u se life. Program s sh ou ld u n dergo con tin -
u ou s evalu ation to m ake su re th e m eth od is bein g
provided well, th at th e su pply lin e is adequ ate, an d
th at cou n selin g an d in form ation al m aterials are sen -
sitive an d accu rate.
10. Women must have access to removal on demand or
when the approved duration of use is reached
Becau se Jadelle is a provider-depen den t m eth od,
wom en can n ot in itiate or discon tin u e u se of th e con -
traceptive by th em selves. Wom en w h o ch oose
Jadelle m u st be assu red th at th ey can obtain
rem ovals on requ est, w ith ou t restriction s, by
providers wh o h ave u n dergon e train in g or retrain -
in g. Th e fees wom en pay at th e tim e of in sertion
sh ou ld also cover th e later cost of rem oval. Program s
m u st h ave a plan for clien t record keepin g an d fol-
low-u p to an ticipate fu tu re dem an d for rem oval, an d
th ey m u st attem pt to locate clien ts wh o do n ot
retu rn on th eir own . In form ation m aterials an d
cou n selin g m u st em ph asize th e reason s for rem oval
at five years an d stipu late th at a wom an h as th e righ t
to rem oval at an y tim e. Th is in form ation sh ou ld be
repeated du rin g follow-u p visits to en su re th at th e
wom an is aware th at sh e m u st retu rn for rem oval at
th e en d of Jadelle’s approved u se life.
11. Early removal should not automatically be viewed
as failure of the method
A wom an can ch oose to u se Jadelle for th e fu ll u se
life, bu t sh e sh ou ld be free to h ave it rem oved at an y
tim e with ou t h avin g to ju stify h er requ est. Her
ch oice to h ave th e rods rem oved early does n ot n ec-
essarily m ean th e m eth od h as failed h er. Sh e m ay
wan t to becom e pregn an t; h er lifestyle m ay h ave
ch an ged; or sh e m ay wan t to discon tin u e becau se
sh e is u n h appy with th e m eth od. Good cou n selin g
prior to selection of Jadelle will m in im ize later rejec-
tion of th e im plan t system .
12. The program’s efforts should focus on meeting the
woman’s needs
Th e in trodu ction of a n ew m eth od provides an
opportu n ity to h elp in dividu al clien ts ach ieve th eir
reprodu ctive in ten tion s in a h ealth fu l m an n er. Th e
m an n er in wh ich services are offered, alon g with
th e in trin sic properties of th e m eth od, will sh ape
u sers’ perception s an d experien ces with Jadelle.
Clien t feedback abou t experien ces with th e m eth od
is an in valu able tool for providers an d program
m an agers.
13. All contraceptives should be provided ethically
Users of fam ily plan n in g services sh ou ld be assu red
th at th eir con versation s an d records will be kept
strictly con fiden tial an d th at th ey will be given th e
opportu n ity for in form ed ch oice an d in form ed con -
sen t. A private location sh ou ld be provided for cou n -
selin g abou t Jadelle.
21
A N SWERS TO FREQUEN TLY A SKED QUESTION S
A BOUT JA D ELLE
Th is discu ssion can be u sed by h ealth care providers
as a cou n selin g tool. Wh ile it can also offer u sefu l
in form ation to poten tial Jadelle u sers, it sh ou ld n ot
take th e place of cou n selin g by h ealth care providers.
Ge n e ral in fo rm atio n
1. What is Jadelle?
Jadelle is an im plan t system th at provides effective,
lon g-actin g, reversible con traception for wom en .
Two th in , flexible rods m ade of silicon e tu bin g an d
filled with levon orgestrel, a syn th etic progestin , are
in serted ju st u n der th e skin of a wom an ’s u pper,
in n er arm in a m in or su rgical procedu re. Protection
from pregn an cy is provided with in 24 h ou rs, wh en
in sertion is perform ed du rin g th e first week of a
w om an ’s m en stru al cycle. Th e w om an rapidly
retu rn s to h er n orm al fertility wh en th e im plan ts are
rem oved. Becau se Jadelle con tain s n o estrogen , th e
m ost com m on side effects are ch an ges in m en stru al
bleedin g pattern s. Most oth er com m on side effects
are sim ilar to th ose experien ced by wom en wh o u se
oth er h orm on al con traceptives.
2. What is Jadelle made of?
Th e ou ter part of th e Jadelle rod is silicon e ru bber
tu bin g, sim ilar to th e m aterial u sed in cath eters an d
h eart valves sin ce th e 1950s. It also is th e sam e kin d
of m aterial u sed in Norplan t capsu les, an oth er con -
traceptive im plan t system . Th e rods release levo-
n orgestrel, a syn th etic progestin th at h as been u sed
in com bin ed oral con traceptives an d in progestin -
on ly pills for m ore th an 30 years. Wh at is “n ew”
abou t th e rods is th eir delivery system , wh ich can
provide con traceptive protection for u p to five years.
3. How do Jadelle rods differ from Norplant capsules?
Th e Jadelle system con sists of two rods, wh ile th e
Norplan t system h as six capsu les. Becau se th ere are
fewer im plan ts, Jadelle is easier to in sert an d rem ove
than Norplant. Rods differ from capsules. Each Jadelle
rod is 43 millimeters long and 2.5 millimeters in diam-
eter, slightly longer (one centimeter) and slightly thick-
er (0.1 m illim eter) th an each Norplan t capsu le. Each
rod con tain s 75 m g of levon orgestrel for a total of 150
22
m g, wh ile th e six Norplan t capsu les each con tain 36
m g, for a total of 216 m g. Both th e capsu les an d rods
h ave ou tside sh eath s com posed of silicon e ru bber, bu t
th ey are m ade differen tly. In th e Norplan t capsu le,
levon orgestrel crystals are packed with in th e ru bber
sheath, which is then sealed at each end. In the Jadelle
rod, a core of m ixed levon orgestrel an d elastom er (a
polym er h avin g th e elastic properties of n atu ral ru b-
ber) is en closed with in th e ru bber sh eath , wh ich is
th en sealed at each en d with m edical adh esive.
4. How effective is Jadelle in preventing pregnancy?
Jadelle is on e of th e m ost effective reversible con tra-
ceptives available. Th e cu m u lative pregn an cy rate in
clin ical trials was 0.3 for th ree years an d 1.1 percen t
for five years. Jadelle h as a lower failu re rate th an
th e pill an d m ost IUDs. Its efficacy is com parable to
th at of su rgical sterilization .
5. For how long is Jadelle effective?
Th e U.S. Food an d Dru g Adm in istration (FDA) in i-
tially approved Jadelle for th ree years’ u se. In Ju ly
2001 th e FDA sen t an approvable letter for exten sion
of u se to five years. Th e m eth od is approved for five
years in Fin lan d an d oth er Eu ropean cou n tries, an d
for th ree years in In don esia an d Th ailan d. Data for
both th ree an d five years are in clu ded in th is section .
6. How does Jadelle work?
Pregn an cy is preven ted in Jadelle u sers by a com bi-
n ation of m ech an ism s. Th e m ost im portan t are th e
in h ibition of ovu lation an d th e th icken in g of th e cer-
vical m u cu s, m akin g it im perm eable to sperm . Oth er
m ech an ism s m ay add to th ese con traceptive effects.
7. When was Jadelle approved?
Jadelle was approved for m arketin g as a th ree-year
m eth od in th e Un ited States in 1996 an d in Fin lan d
in 1997. In 2000, Fin lan d approved th e exten sion
of u se of th e m eth od to five years. In 2001, th e FDA
sen t an approvable letter for exten sion of u se to five
years.
8. Who can use Jadelle?
Alm ost an y fertile wom an with ou t con train dication s
(see below) wh o wan ts to avoid pregn an cy m ay u se
Jadelle. Th e m eth od is su itable for wom en wh o are
seekin g con tin u ou s, yet reversible con traception ;
wh o wan t to space th eir ch ildren ; wh o can n ot u se
m eth ods th at con tain estrogen ; wh o do n ot wan t to
be sterilized; an d/ or wh o desire a m eth od th at is con -
ven ien t an d n ot related to sexu al in tercou rse.
9. Who should not use Jadelle?
Jadelle sh ou ld n ot be u sed by wom en wh o are preg-
n an t or wh o h ave an y of th ese con train dication s:
active th rom boph lebitis or th rom boem bolic disor-
ders, su ch as blood clots in th e legs, lu n gs, or eyes;
u n diagn osed abn orm al gen ital bleedin g; acu te liver
disease; n on can cerou s or can cerou s liver tu m ors;
kn own or su spected breast can cer; a h istory of idio-
path ic in tracran ial h yperten sion ; or h ypersen sitivity
to levon orgestrel or an y of th e oth er com pon en ts of
th e rods (e.g., silicon e elastom er). Wom en wh o h ave
h ad previou s blood clots or oth er th rom boem bolic
disorders sh ou ld con su lt with th eir h ealth care
providers abou t wh eth er to u se th e m eth od.
10. Is Jadelle effective for women of differing weights?
Yes. Even am on g h eavier wom en , an n u al pregn an cy
rates for Jadelle u sers over th ree years an d five years
are well below th ose of oral con traceptives. A com -
parative five-year stu dy of Jadelle an d Norplan t
u sers sh owed n o sign ifican t effect of weigh t on preg-
n an cy risk.
11. What do women like most about Jadelle?
Discussions with women using Jadelle in various
countries show they like the method’s reliability, con-
venience, effectiveness, and reversibility. Other advan-
tages mentioned are the method’s long-term duration
and the fact that the rods are placed in the arm.
12. What do women dislike about Jadelle?
Th e side effect th at wom en like least is m en stru al
irregu larity, wh ich can m ean h eavy or prolon ged
bleedin g, spottin g, or n o bleedin g at all. Th is kin d of
irregu lar bleedin g occu rs becau se th e m eth od con -
tain s n o estrogen . Wh ile su ch irregu lar bleedin g is
u su ally n o cau se for alarm , it can be trou blesom e for
som e wom en . In addition , wom en com plain abou t
side effects com m on to oth er h orm on al m eth ods,
su ch as weigh t gain , h eadach es, acn e, an d m ood
ch an ges. Som e rod u sers are an xiou s abou t possible
pain an d com plication s from th e in sertion an d
rem oval procedu res. Sin ce th e Jadelle system is n ot
u ser-con trolled, it is im portan t th at wom en be able
to requ est rem oval an d receive it prom ptly from
com peten t providers.
13. How many Jadelle users continue past the first year?
In th e clin ical stu dies on wh ich approval was based,
cu m u lative con tin u ation rates were 88.3 percen t
after th e first year, 60.6 percen t after th ree years, an d
41.5 percen t at five years. Th ese figu res m ay vary.
You n ger wom en h ave lower con tin u ation rates;
older wom en , wh ose fam ilies are com pleted, h ave
h igh er con tin u ation rates.
14. Why do women discontinue using this method?
Wom en discon tin u e u sin g Jadelle becau se of side
effects, becau se th ey wan t to becom e pregn an t, or
for oth er person al reason s. Stu dies con du cted by th e
Popu lation Cou n cil in dicate th at, over a th ree-year
period, 14.1 per 100 wom en stopped u sin g Jadelle
becau se of m en stru al irregu larities an d 14.7 per 100
wom en discon tin u ed for oth er m edical reason s; 9.7
per 100 wom en did n ot con tin u e for th e fu ll th ree
years becau se th ey were plan n in g a pregn an cy.
Medical occu rren ces m ost frequ en tly cited as reason s
for rem oval were h eadach es, depression , weigh t
gain , or h air loss.
15. Why is counseling important?
Stu dies h ave sh own th at wom en wh o receive good
cou n selin g are m ore satisfied with th e m eth od th ey
adopt an d are m ore likely to con tin u e u sin g it.
Con traceptive u sers wh o believe th ey h ave been
fu lly an d accu rately in form ed abou t th eir ch oices
will feel m ore con fiden t abou t th eir m eth ods an d
th eir providers. In adequ ate cou n selin g abou t Jadelle
m ay resu lt in early rem ovals an d loss of con tracep-
tive protection .
16. What topics should be covered in counseling?
Th e Jadelle u ser sh ou ld kn ow th e m ost im portan t
facts before th e rods are in serted: h ow th e m eth od
works, an y discom fort sh e m igh t feel followin g th e
in sertion procedu re, wh at side effects sh e m igh t
en cou n ter, th e likelih ood of failu re, h ow to recog-
n ize warn in g sign s of possible com plication s, an d
wh en to h ave th e rods rem oved. Sh e sh ou ld also
learn h ow th e m eth od com pares with oth er available
con traceptives. Jadelle u sers sh ou ld kn ow th at m ost
23
in sertion s an d rem ovals are easily accom plish ed
wh en perform ed by train ed h ealth care providers
an d are n ot pain fu l for m ost wom en .
17. Does the age of the user matter?
Alth ou gh wom en from ages 18 to 40 years partici-
pated in th e clin ical trials, wom en you n ger an d older
th an th ose ages also can u se Jadelle. If th ere are n o
con train dication s, th e rods m ay be u sed by wom en
th rou gh ou t th eir reprodu ctive years. Several stu dies
of Norplan t u se by teen agers in th e Un ited States
h ave sh own th e m eth od to be effective an d well
accepted. Alth ou gh th ere are n o stu dies specific to
older w om en , w om en can u se Jadelle as th ey
approach m en opau se.
In se rtio n an d re m o val
18. Should a woman undergo a physical exam before
receiving Jadelle?
It is recom m en ded bu t n ot essen tial th at a wom an
con siderin g Jadelle u n dergo a m edical exam in ation .
Th is m ay in clu de givin g a m edical h istory an d h av-
in g a pelvic exam to en su re th at sh e h as n o diseases
or con dition s th at wou ld m ake it u n safe for h er to
u se th is m eth od.
19. Can Jadelle be inserted at any time?
To m ake su re th e wom an is n ot pregn an t, Jadelle
rods sh ou ld be in serted with in seven days after th e
on set of m en stru al bleedin g or im m ediately follow-
in g an abortion . If Jadelle im plan ts are in serted at
an y oth er tim e in th e m en stru al cycle, th e possibili-
ty of a preexistin g pregn an cy m u st be ru led ou t an d
a n on h orm on al con traceptive m eth od (su ch as con -
dom s, sperm icides, or diaph ragm s) m u st be u sed for
at least seven days followin g in sertion to avoid preg-
n an cy. If ovu lation an d con ception h ave already
occu rred before Jadelle is in serted, pregn an cy cou ld
occu r du rin g th e m on th followin g in sertion .
20. How are the rods inserted?
Th e rods are in serted u n der th e skin of th e in n er side
of th e u pper arm in a m in or su rgical procedu re. In
som e cou n tries, a pre-loaded disposable in serter
(developed by Leiras) is available. Elsewh ere, th e
rods are loaded in a reu sable h ollow n eedle called a
trocar. In eith er tech n iqu e, a local an esth etic is
24
in jected an d th e clin ician m akes a sm all in cision —
abou t 3 m m lon g—u sin g eith er th e disposable in sert-
er or th e trocar. Th e rods are placed su bderm ally in
th e sh ape of a V open in g toward th e sh ou lder. Th e
procedu re sh ou ld take on ly a few m in u tes. Often th e
on ly pain is associated with th e in jection of th e an es-
th etic. Usu ally th e in cision does n ot requ ire stitch es
an d is covered with a sm all adh esive ban dage an d
protective gau ze ban dage.
21. Who performs the insertions?
Th e rods sh ou ld be in serted by h ealth care providers
w h o h ave received train in g in th e procedu re.
Gen erally, an y train ed ph ysician , n u rse, n u rse-m id-
wife, or oth er h ealth care provider can perform th e
in sertion .
22. What kind of complications are possible?
Th e n eedle providin g th e an esth etic m ay stin g briefly.
Rarely, wom en m ay h ave reaction s to th e an esth etic
u sed. Wh en th e an esth etic wears off, th ere m ay be
ten dern ess as well as discoloration , bru isin g, an d/ or
swellin g in th e area of th e in sertion for a few days
after placem en t. Th ere h ave also been reports of arm
pain , n u m bn ess, an d tin glin g followin g placem en t.
Du rin g Jadelle clin ical trials, in fection at th e in sertion
site occu rred in 0.4 percen t of wom en over five years.
Atten tion to aseptic tech n iqu e an d proper in sertion
an d rem oval of Jadelle rods redu ce th e possibility of
in fection . In som e w om en , h yperpigm en tation
occu rs over th e im plan tation site, bu t th is effect is
u su ally reversed followin g rem oval. Du rin g postm ar-
ketin g u se of Norplan t, oth er cu tan eou s reaction s
reported in clu de blisterin g, u lceration s, an d slou gh -
in g. Th ere h ave been reports of n erve in ju ry with
Norplan t, m ost com m on ly associated with deep
placem en t an d rem oval. Expu lsion of Norplan t
im plan ts h as been reported, m ore frequ en tly wh en
im plan t placem en t was sh allow or too close to th e
in cision or wh en in fection was presen t.
23. How should the insertion site be cared for?
Th e in sertion site sh ou ld n ot be bu m ped for a few
days an d th e area sh ou ld be kept dry. Also, th e
wom an sh ou ld avoid h eavy liftin g for two to th ree
days after th e in sertion . Th e protective gau ze ban -
dage sh ou ld be left in place for th ree days an d th e
sm all adh esive ban dage sh ou ld be left on for a day or
two lon ger. Som e wom en h ave reaction s to th e
adh esive of th e ban dage.
24. Are Jadelle rods visible?
Sin ce th e in cision is sm all, m ost wom en do n ot h ave
a n oticeable scar. Th e rods are u su ally com fortable
an d barely visible. Wh en th ey are visible, th e ou tlin e
of th e rods can be seen u n der th e skin an d th ey
resem ble colorless vein s.
25. Will the rods move around?
Th e rods’ location m ay sh ift. Th ere h ave been rare
postm arketin g reports of m ovem en t of Norplan t cap-
su les. Most of th e m ovem en t in volved m in or
ch an ges in th e position in g of th e im plan ts, bu t som e
h ave in volved sign ifican t displacem en t of u p to sev-
eral in ch es. Som e of th ese reported displacem en ts
h ave been associated with pain an d su bsequ en t dif-
ficu lt rem oval of Norplan t.
26. Can a woman work after the insertion?
Yes. Sh e can resu m e h er n orm al work an d dom estic
activities, as lon g as sh e does n ot bu m p th e site,
avoids h eavy liftin g, an d keeps th e in cision site dry
for at least th ree days. Th e wom an does n ot h ave to
be con cern ed if pressu re is pu t on th e area du rin g
n orm al activities. After th e in cision h as h ealed, th e
skin over th e rods can be tou ch ed at an y tim e.
27. How soon after insertion can a couple have sexual
relations?
Th is depen ds on wh en in h er m en stru al cycle a
wom an h as th e rods in serted. If Jadelle rods are
in serted du rin g a wom an ’s m en ses (to en su re sh e is
n ot pregn an t at th e tim e of in sertion ), th e cou ple
m ay h ave sexu al relation s with ou t a back-u p con tra-
ceptive m eth od 24 h ou rs after th e in sertion . If th e
rods are in serted at an y oth er tim e du rin g th e cycle,
th e possibility of a preexisitin g pregn an cy m u st be
ru led ou t an d a n on h orm on al con traceptive m eth od
sh ou ld be u sed for at least seven days followin g th e
procedu re to avoid pregn an cy. If a wom an does get
pregn an t, th e rods m u st be rem oved.
28. When should the woman return to the clinic for a
checkup?
Th e follow-u p sch edu le depen ds on th e practice of
th e particu lar clin ic or ph ysician ’s office in wh ich a
wom an receives th e rods. Sh e m ay be asked to
retu rn for periodic h ealth ch ecku ps or to report on
h er experien ce with th e rods. Sh e sh ou ld be en cou r-
aged to retu rn to th e sam e provider or clin ic if sh e
h as an y h ealth problem s th at worry h er; if sh e wish -
es to becom e pregn an t; or if sh e is m ovin g an d n eeds
th e address of a clin ic th at provides Jadelle in h er
n ew area. An n u al ch ecku ps offer an occasion to
rem in d wom en wh en to h ave th eir rods rem oved,
bu t are n ot requ ired.
29. How is Jadelle’s protection reversed?
On e of th e m ost im portan t ch aracteristics of Jadelle
is its reversibility. Th e con traceptive action stops
with in two to th ree days after rem oval of th e rods.
Th e rods are rem oved du rin g a clin ical procedu re
u n der a local an esth etic, sim ilar to th e in sertion
process. An altern ative form of con traception sh ou ld
be u sed as soon as th e rods are rem oved, u n less th e
wom an desires pregn an cy.
30. When should Jadelle be removed?
The rods should be removed at the end of the
approved duration of use—either five or three years.
However, the woman should be able to request and
obtain removal of the rods at any time, for any reason.
31. What happens if the rods are not removed after the
approved period of use?
Data h ave sh own th at wom en are protected for u p to
five years. If th e rods are n ot rem oved at five years,
th e risks of pregn an cy an d of ectopic pregn an cy
in crease.
32. Who should remove the rods?
Health care providers experien ced in rem ovals
sh ou ld perform th e procedu re. Th e rods can be
rem oved at th e sam e clin ic or office wh ere th ey were
in serted or at an oth er h ealth facility th at offers th e
m eth od. Before in sertion , a wom an sh ou ld con firm
th at sh e will h ave access to a com peten t provider at
rem oval tim e.
33. Is removal painful?
Just as when the capsules are inserted, the health pro-
fessional will apply a local anesthetic to prevent pain,
but the anesthetic injection itself may hurt briefly. If
the rods have been inserted properly, removal should
be rapid and uncomplicated. When the anesthetic
wears off, there may be some tenderness, discol-
25
oration, bruising, and swelling in the area for a few
days. It is neither necessary nor recommended that
general anesthesia be used for this procedure.
34. Are removals more difficult than insertions?
Yes. Alth ou gh m ost rem ovals are n ot difficu lt, th e
procedu re u su ally takes lon ger th an in sertion . Som e
rods m ay be h arder th an oth ers to locate an d rem ove
if th ey were in serted too deeply or if tem porary
swellin g of th e arm occu rs du rin g rem oval. A sm all
in cision abou t 4 m m lon g will be m ade, th rou gh
wh ich both rods are rem oved. If th e clin ician is
u n able to rem ove both rods du rin g on e procedu re,
th e wom an sh ou ld retu rn after h er arm h eals.
Wom en sh ou ld be in form ed of th e possibility of
n eedin g a su bsequ en t visit for rem oval an d sh ou ld
n ot be alarm ed if th is is n ecessary. Clin ician s sh ou ld
feel th e in sertion site to be su re th ey can locate both
rods before attem ptin g to rem ove th em . If th ey can -
n ot be felt, th e rods can be located th rou gh x-ray,
u ltrasou n d, or com pression m am m ograph y, all of
wh ich are pain less procedu res. Rem oval com plica-
tion s or difficu lties were reported in 7.5 percen t of
m ore th an 1,100 wom en wh o h ad Jadelle rem oved.
Com plication s (som e related to deep placem en t)
in clu ded m u ltiple or lon g in cision s, bru isin g, dis-
placem en t, pain , prolon ged rem oval, in com plete
rem oval requ irin g an addition al visit or visits, broken
im plan ts, an d fibrou s pericapsu lar tissu e.
35. How should a woman care for the site after
removal?
As with in sertion , it is im portan t to avoid bu m pin g
th e rem oval site for a few days. Th e area sh ou ld be
kept clean , dry, an d ban daged u n til h ealed (3 to 5
days) so th at th e site does n ot becom e in fected.
36. How soon after removal can a woman become
pregnant?
Th e reversibility of protection afforded by Jadelle is
on e of th e advan tages of th e m eth od. On ce th e rods
are rem oved, th e con traceptive effect wears off with -
in a few days.
37. Can another set of rods be inserted when the old set
is removed?
Yes. If a wom an wan ts to con tin u e u sin g Jadelle, a
n ew set can be in serted wh en th e old set is rem oved.
Or a wom an can u se Norplan t an d th en switch to
26
Jadelle. Th e secon d set can be placed th rou gh th e
in cision from wh ich th e earlier set was rem oved or
in th e oth er arm . If a wom an does n ot wan t to con -
tin u e with th e rods an d does n ot wan t to becom e
pregn an t, sh e sh ou ld be offered an oth er con tracep-
tive m eth od before sh e leaves th e clin ic.
Sid e e ffe cts an d h e alth co n sid e ratio n s
38. What are the most common side effects reported
with Jadelle use?
Th e m ost com m on side effect of Jadelle u se is irreg-
u lar m en stru al bleedin g—m ost wom en can expect
som e variation in m en stru al bleedin g pattern s.
Irregu larities vary from wom an to wom an an d m ay
in clu de prolon ged m en stru al bleedin g (m ore days
th an a wom an wou ld n orm ally experien ce), h eavy
bleedin g, prolon ged spottin g or spottin g between
periods, n o bleedin g at all, or a com bin ation of th ese
pattern s.
Oth er adverse reaction s reported by 10 percen t
or m ore of wom en du rin g five years of Jadelle u se in
clin ical trials were application site reaction , discol-
oration , or pain ; dizzin ess; h eadach e; leu korrh ea
(wh itish disch arge from th e vagin a an d u terin e cav-
ity); m astalgia (breast pain ); n au sea; pelvic pain ; u ri-
n ary tract sym ptom s; vagin itis (in clu din g gen ital
pru ritu s an d in fection s); an d weigh t gain .
Wom en u sin g Jadelle h ave also experien ced
acn e, appetite ch an ges, con tact derm atitis, h air loss,
lesion s or in flam m ation of th e cervix, libido
decrease, an d n ervou sn ess.
Preexistin g con dition s of acn e or excessive
grow th of body or facial h air cou ld w orsen .
Occasion ally, an in fection m ay occu r at th e im plan t
site (treatable with an an tibiotic), or th ere m ay be a
brief in ciden ce of pain or itch in g at th e in sertion site.
Man y of th ese adverse even ts associated with
u se of Jadelle are com m on ly experien ced by u sers of
oth er h orm on al m eth ods.
39. Do most Jadelle users experience side effects?
Yes, alth ou gh it will frequ en tly n ot be clear wh eth er
an adverse even t was cau sed by th e im plan ts. All
con traceptive m eth ods h ave side effects an d Jadelle
is n o exception . Bleedin g irregu larities (in clu din g
spottin g, lon ger or h eavier periods th an previou sly,
or n o bleedin g) are reported by abou t 65 percen t of
rod u sers. A five-year clin ical trial in seven cou n tries
sh owed th at th e two m ost frequ en t m edical reason s,
oth er th an bleedin g irregu larities, leadin g to rem oval
were h eadach e an d weigh t gain . Abou t 19 per 100
wom en discon tin u ed u se of Jadelle becau se of bleed-
in g problem s.
40. Are bleeding irregularities associated with
Jadelle serious?
A ch an ge in th e m en stru al bleedin g pattern —th e
m ost frequ en tly reported side effect—is to be expect-
ed with h orm on al m eth ods th at do n ot con tain
estrogen . Most bleedin g irregu larities associated with
Jadelle are n ot seriou s, alth ou gh th ey m ay be trou -
blesom e for som e u sers. If a wom an experien ces
h eavy bleedin g, sh e sh ou ld see h er ph ysician or
h ealth care provider to m ake su re th e bleedin g is n ot
m askin g an oth er con dition . Becau se som e rod u sers
experien ce am en orrh ea, m issed m en stru al periods
can n ot serve as th e on ly m ean s of iden tifyin g early
pregn an cy.
41. What kind of bleeding pattern can be expected?
It is n ot possible to predict th e kin d of bleedin g pat-
tern a wom an will h ave wh ile u sin g Jadelle. Man y
wom en can expect an altered m en stru al bleedin g pat-
tern to becom e m ore regu lar after six to n in e m on th s.
Both in creased an d redu ced bleedin g ten d to dim in -
ish with tim e, alth ou gh th ese irregu larities can persist
for som e wom en th rou gh ou t th e th ree or five years.
42. Is the lack of bleeding (amenorrhea) harmful?
Som etim es a wom an is con cern ed abou t am en or-
rh ea—th e absen ce of m on th ly bleedin g. A wom an ’s
h ealth or fu tu re fertility will n ot be h arm ed if sh e
does n ot h ave h er period wh ile u sin g Jadelle; th ere
is n o blood “bu ildu p.” Pregn an cy tests sh ou ld be per-
form ed wh en ever a pregn an cy is su spected. Six
weeks or m ore of am en orrh ea after a pattern of reg-
u lar m en ses m ay sign al pregn an cy.
43. Does the use of Jadelle make women anemic?
Despite the increased frequency of menstrual bleeding
in some women using Jadelle, the amount of total blood
loss is usually less than occurs during normal menses. In
some studies, in fact, hemoglobin values of Jadelle users
have been shown to increase. A few rare cases of severe
blood loss have been associated with anemia.
44. Should women be given estrogen to control bleeding
and spotting?
Jadelle is estrogen -free an d m an y wom en an d th eir
h ealth care providers ch oose th e m eth od for th is rea-
son . Alth ou gh research h as been con du cted to test
th e effectiven ess of a few treatm en ts for bleedin g
irregu larities, th ere is n o eviden ce available to pro-
m ote an y specific treatm en t.
45. Does Jadelle use affect lipid and carbohydrate
metabolism?
Seru m lipoprotein levels were altered in th ree clin i-
cal stu dies in volvin g 544 wom en u sin g Jadelle.
Levon orgestrel rod u sers h ad m ean decreases from
baselin e in total ch olesterol, h igh -den sity lipoprotein
(HDL) ch olesterol, an d low -den sity lipoprotein
(LDL) ch olesterol of approxim ately 12 percen t, 14
percen t, an d 10 percen t, respectively. Triglyceride
levels decreased abou t 25 percen t from pretreatm en t
valu es. Alth ou gh th ese decreases were statistically
sign ifican t, all m ean valu es rem ain ed with in th e n or-
m al ran ges. Th e lon g-term clin ical effects of th ese
ch an ges h ave n ot been determ in ed. Wom en wh o are
bein g treated for h yperlipidem ias sh ou ld be followed
closely if th ey elect to u se Jadelle. Som e progestin s
m ay elevate LDL levels, th ereby m akin g th e con trol
of h yperlipidem ias m ore difficu lt.
Th e effect of levon orgestrel-con tain in g im plan ts
on carboh ydrate m etabolism appears to be m in im al.
Du rin g th e Norplan t postm arketin g su rveillan ce
stu dy, diabetes m ellitu s developed in Norplan t u sers
at th e rate of 0.2 per 1,000 wom an -years, a rate n ot
sign ifican tly above th at of con trol su bjects wh o were
n ot u sin g h orm on al con traception . Wh ile th e clin ical
sign ifican ce of th ese fin din gs is u n kn own , diabetic
patien ts sh ou ld be carefu lly observed wh ile u sin g
Jadelle.
46. What are warning signs of possible problems?
A wom an u sin g Jadelle sh ou ld retu rn to h er h ealth
care provider or clin ic im m ediately if sh e h as severe
lower abdom in al pain (possible ectopic pregn an cy),
h eavy vagin al bleedin g (m askin g sym ptom s of cervi-
cal or en dom etrial can cer), delayed m en stru al peri-
ods after several regu lar cycles (possible pregn an cy),
pu s or bleedin g at th e in sertion site (in dication of
in fection ), or expu lsion of an im plan t (wh en place-
m en t is sh allow).
27
 Of cou rse, wom en also sh ou ld seek im m ediate
m edical atten tion if th ey h ave sh arp ch est pain ,
cou gh in g of blood, or su dden sh ortn ess of breath
(possible clot in th e lu n g); pain in th e calf or arm
(possible clot in th e leg or arm ); su dden partial or
com plete loss of vision (possible clot in th e eye);
cru sh in g ch est pain or h eavin ess in th e ch est (possi-
ble h eart attack); su dden severe or persisten t
h eadach e or vom itin g, dizzin ess, or fain tin g, distu r-
ban ces of speech or blu rred vision , weakn ess or
n u m bn ess in an arm or leg (possible stroke or oth er
n eu rological problem ); or sleep disorders, weakn ess,
lack of en ergy, fatigu e, or ch an ges in m ood (possibly
in dicatin g severe depression ).
Th e absen ce of m en stru al periods after several
regu lar cycles m ay be a sign of pregn an cy. If a
wom an is n ot bleedin g at h er expected tim e or h as
lower abdom in al pain or sym ptom s of pregn an cy,
sh e sh ou ld visit th e clin ic with ou t delay. Lower
abdom in al pain m ay in dicate an ectopic pregn an cy.
A change in the frequency, pattern, severity, or
persistence of headaches, or blurred vision, may be
signs of papilledema, which in turn may indicate idio-
pathic intracranial hypertension. Women experienc-
ing these symptoms should discuss them with their
h ealth care provider, wh o may screen th em for
papilledema and, if the condition is present, refer
them to a neurologist for further diagnosis and care.
This condition, which is seen most commonly in obese
women of reproductive age in the general population,
has been reported in postmarketing use of Norplant in
the United States and the United Kingdom. However,
a causal relationship is unclear. Jadelle rods should be
removed from women experiencing papilledema.
Con tact len s wearers wh o experien ce visu al
ch an ges or ch an ges in len s toleran ce wh ile u sin g
Jadelle sh ou ld be assessed by an oph th alm ologist.
Wom en wh o becom e sign ifican tly depressed
wh ile u sin g Jadelle sh ou ld discu ss with th eir h ealth
care provider wh eth er th e rods sh ou ld be rem oved.
47. Are there other health considerations with
Jadelle use?
Wom en with certain h ealth con dition s can u se
Jadelle, provided th ey h ave regu lar ch ecku ps. If a
wom an h as an y of th e followin g con dition s, sh e
sh ou ld discu ss th em with h er h ealth care provider
before u sin g th e rods: breast n odu les, fibrocystic dis-
28
ease of th e breast, or an abn orm al breast x-ray or
m am m ogram ; diabetes; elevated ch olesterol or
triglycerides; h igh blood pressu re; m igrain e or oth er
h eadach es; epilepsy; m en tal depression ; gallbladder,
h eart, or kidn ey disease; or a h istory of blood clots,
h eart attack, or stroke.
48. Does Jadelle cause heart or vascular problems?
Th ere h ave been reports of su perficial ph lebitis in
clin ical trials of Jadelle an d postm arketin g reports of
th rom boph lebitis an d su perficial ph lebitis coin ciden t
with Norplan t u se, m ore com m on ly in th e arm of
in sertion . In su ch cases, th e im plan ts sh ou ld be
rem oved. Rem oval sh ou ld also be con sidered in
wom en wh o will be su bjected to prolon ged im m obi-
lization becau se of su rgery or illn ess. Th ere h ave also
been reports of oth er th rom boem bolic disorders an d
cardiovascu lar problem s (su ch as stroke, m yocardial
in farction , pu lm on ary em bolism , an d deep-vein
th rom bosis) coin ciden t with Norplan t u se. In th e
Norplan t postm arketin g su rveillan ce stu dy, wh ich
observed m ore th an 30,000 w om an -years of
Norplan t u se an d com parable experien ce in wom en
n ot u sin g h orm on al con traception , n o m yocardial
in farction s occu rred in eith er grou p. It is expected
th at th is experien ce applies equ ally to Jadelle.
An in creased risk of th rom boem bolic an d
th rom botic disease (pu lm on ary em bolism , su perfi-
cial ven ou s th rom bosis, an d deep-vein th rom bosis)
h as been associated with th e u se of com bin ation oral
con traceptives. Com bin ed oral con traceptives, wh ich
con tain both estrogen an d progestin , h ave been
sh own to in crease both th e relative an d attribu table
risks of th rom botic an d h em orrh agic strokes,
alth ou gh th e risk is greatest am on g wom en over 35
years of age wh o are h yperten sive (h ave h igh blood
pressu re) an d also sm oke.
49. Does Jadelle use increase blood pressure?
In creased blood pressu re h as been reported in u sers
of com bin ed oral con traceptives. Th e prevalen ce of
elevated blood pressu re in creases with lon g expo-
su re. Alth ou gh n o clin ically sign ifican t rises in m ean
blood pressu re occu rred am on g Jadelle u sers in clin -
ical trials, ph ysician s sh ou ld be aware of th e possibil-
ity of elevated blood pressu re in wom en u sin g th is
m eth od. In th e Norplan t postm arketin g su rveillan ce
stu dy, th e in ciden ce of h yperten sion an d borderlin e
h yperten sion was m oderately h igh er in Norplan t
u sers com pared with wom en in th e con trol grou ps.
Becau se Norplan t u sers h ad m ore frequ en t blood
pressu re m easu rem en ts th an con trols, th e resu lts
m igh t partially reflect a reportin g bias.
50. Does Jadelle cause autoimmune diseases?
Au toim m u n e diseases su ch as scleroderm a, system ic
lu pu s, an d rh eu m atoid arth ritis occu r in th e gen eral
popu lation an d m ore frequ en tly am on g wom en of
ch ildbearin g age. Th ere h ave been rare reports of
variou s au toim m u n e diseases, in clu din g th e on es
listed above, in u sers of th e six-capsu le Norplan t
im plan ts; h owever, th e rate of reportin g is sign ifi-
can tly lower th an th e expected in ciden ces for th ese
diseases in th e gen eral popu lation . Stu dies h ave
raised th e possibility of an tibodies bein g developed
again st silicon e-con tain in g devices; h owever, th e
specificity an d clin ical relevan ce of th ese an tibodies
are u n kn own . Wh ile it is believed th at th e occu r-
ren ce of au toim m u n e diseases am on g Norplan t cap-
su le u sers is coin ciden tal, h ealth care providers
sh ou ld be alert to th e earliest m an ifestation s of su ch
diseases in Jadelle u sers. In th e Norplan t postm ar-
ketin g su rveillan ce stu dy, n o sign ifican t differen ce in
th e risk of au toim m u n e disease was fou n d between
Norplan t u sers an d u sers of n on h orm on al m eth ods.
51. Does Jadelle use increase the risk of gallbladder disease?
Som e stu dies h ave reported an in creased lifetim e rel-
ative risk of gallbladder disease in u sers of oral con -
traceptives an d estrogen s. More recen t stu dies, h ow-
ever, h ave sh own th at th e relative in creased risk of
developin g gallbladder disease am on g oral con tra-
ceptive u sers is m in im al. Th ese recen t fin din gs m ay
be related to th e lower doses of estrogen s an d pro-
gestin s in cu rren t pill form u lation s. In th e Norplan t
postm arketin g su rveillan ce stu dy, th e relative risk of
gallbladder disease w as m oderately h igh er in
Norplan t u sers in Ch ile an d Ch in a com pared with
wom en in th e con trol grou ps.
52. Does Jadelle cause birth defects?
Exten sive epidem iological stu dies h ave revealed n o
in creased risk of birth defects in th e ch ildren of
wom en wh o h ave u sed oral con traceptives before
pregn an cy. Stu dies also fail to su ggest a teratogen ic
effect, particu larly in sofar as cardiac an om alies an d
lim b-redu ction defects are con cern ed, wh en oral
con traceptives are u sed in adverten tly du rin g early
pregn an cy. Th ere is n o eviden ce su ggestin g th at th e
risk associated with Jadelle or Norplan t u se is differ-
en t from th e risk associated with oral con traceptives.
There were no reports of birth defects for the live
births that occurred during use of Jadelle in clinical
trials. However, in postmarketing use of Norplant cap-
sules, congenital anomalies have been reported in the
offspring of women who used the method inadver-
tently during early pregnancy. A cause and effect rela-
tion sh ip h as n ot been establish ed. If a wom an
becom es pregn an t wh ile u sin g Jadelle, th e rods
should be removed immediately.
53. Can a smoker use Jadelle?
Cigarette sm okin g in creases th e risk of h eart attacks
an d strokes in u sers of com bin ed oral con traceptives.
Th is risk in creases with age an d with h eavy sm okin g
(15 or m ore cigarettes a day) an d is qu ite m arked in
wom en over 35 years old. Wh ile th is is believed to be
an estrogen -related effect, it is n ot kn own wh eth er a
sim ilar risk exists with progestin -on ly m eth ods su ch
as Jadelle. A wom an wh o ch ooses to u se Jadelle is
advised n ot to sm oke.
54. Does Jadelle protect against sexually transmitted
diseases?
No. Th is form of con traception does n ot protect
again st HIV/ AIDS or oth er sexu ally tran sm itted dis-
eases. If a wom an wh o elects to u se Jadelle th in ks
sh e m igh t be at risk for STDs, sh e or h er partn er
sh ou ld u se a con dom in addition to th e rods.
55. Does Jadelle cause cancer at the incision site?
In rare in stan ces can cers h ave occu rred at th e site of
foreign -body in tru sion s or old scars. Non e h ave been
reported in Norplan t u sers or in clin ical trials with
Jadelle. In roden ts, wh ich are h igh ly su sceptible to
su ch can cers, th e in ciden ce decreases with decreas-
in g size of th e foreign body. Becau se of th e resistan ce
of h u m an s to th ese can cers an d becau se of th e sm all
size of th e im plan ts, th e risk to u sers of Jadelle is
ju dged to be m in im al.
56. Can a woman use Jadelle if she is breastfeeding?
Horm on es are n ot con sidered th e m ost appropriate
con traceptives for breastfeedin g wom en . However,
stu dies h ave sh own n o sign ifican t effects on th e
29
growth or h ealth of in fan ts wh ose n u rsin g m oth ers
began u sin g levon orgestrel im plan ts five to seven
weeks after ch ildbirth . Th ere is n o experien ce to su p-
port th e u se of Jadelle earlier th an six weeks after
ch ildbirth in lactatin g wom en .
57. Is sickle cell anemia a contraindication?
Sickle cell an em ia is n ot con sidered a con train dica-
tion for th e u se of Jadelle. However, th e Popu lation
Cou n cil does n ot h ave relevan t data from clin ical tri-
als sin ce wom en wh o were an em ic were n ot in clu d-
ed in th e Cou n cil’s stu dies with Norplan t capsu les or
with Jadelle. On e pu blish ed stu dy in dicated th at
wom en with sickle cell an em ia did n ot su ffer adverse
effects wh en u sin g Norplan t capsu les.
58. Do other drugs interact with Jadelle?
Certain dru gs m ay in teract with th e h orm on e deliv-
ered by Jadelle to m ake th e rods less effective in pre-
ven tin g pregn an cy. Th ese in clu de dru gs u sed for
epilepsy su ch as ph en ytoin (like Dilan tin ), carba-
m azepin e, an d oxcarbazepin e. Wh en con siderin g
Jadelle u se, a wom an sh ou ld tell h er h ealth care
provider if sh e is takin g an y of th ese or oth er m ed-
ication s. Rifam pin is kn own to decrease th e effec-
tiven ess of com bin ation oral con traceptives; its effect
on levon orgestrel con cen tration s is u n kn own .
59. Is there a risk of ectopic pregnancy?
The absolute risk of ectopic pregnancy (a fetus devel-
oping outside the uterus) during use of Jadelle is very
low, because of the high effectiveness of the method.
Ectopic pregnancies occur with Jadelle at a rate of less
than 0.5 per 1,000 woman-years. Clinical and con-
trolled postm arketin g stu dies of Norplan t u sers
showed no increase in the rate of ectopic pregnancies
per year as compared with women using IUDs, oral
con traceptives, con dom s, or n o m eth od at all.
Physicians should be alert to the possibility of an
ectopic pregnancy among women using Jadelle who
become pregnant or complain of lower abdominal
pain. Any patient who presents with lower abdominal
pain must be evaluated to rule out ectopic pregnancy.
60. Are ovarian cysts a problem for Jadelle users?
Fu n ction al ovarian cysts or en larged follicles occu r in
levon orgestrel im plan t u sers m ore frequ en tly th an
th ey do in wom en wh o do n ot u se Jadelle or
Norplan t. If follicles becom e en larged, th ey m ay pro-
30
du ce som e discom fort in som e wom en , alth ou gh
m ost u sers wou ld n ot be aware of th em u n less th ey
were fou n d du rin g a ph ysical exam . In th e m ajority
of wom en affected, en larged follicles will spon ta-
n eou sly disappear an d do n ot requ ire su rgery.
Rarely, th ey m ay twist or ru ptu re, som etim es cau s-
in g abdom in al pain , so th at su rgery is requ ired.
61. Are there known long-term side effects?
No stu dies of lon g-term h ealth effects from eith er
Jadelle or Norplan t u se h ave been con du cted beyon d
five years. However, th e dru g con tain ed in both
types of im plan ts—levon orgestrel—h as been u sed in
oral con traceptives for over 30 years.
62. What is known about medium-term health effects
of Jadelle use?
Th e best eviden ce of m ediu m -term h ealth effects
com es from th e five-year Norplan t postm arketin g
su rveillan ce. Th e su rveillan ce com pared som e 8,000
Norplan t u sers with abou t 8,000 u sers of eith er IUDs
or sterilization in eigh t developin g cou n tries. Th e
wom en were followed for five years, even if th ey dis-
con tin u ed u se of th e m eth od, switch ed to an oth er,
or becam e pregn an t. Norplan t was n ot associated
with an y m aterial risk of m ajor m orbidity com pared
with th e two con trol grou ps. For greater detail, see
th e section on th e postm arketin g su rveillan ce in th is
m on ograph .
Re se arch an d d e ve lo p m e n t
63. Why was Jadelle developed?
Th e Popu lation Cou n cil developed Jadelle to provide
th e sam e level of con traceptive protection as
Norplan t wh ile u sin g fewer im plan ts, th ereby m ak-
in g th e m eth od easier to in sert an d rem ove.
64. Why are additional contraceptives needed?
Th ere is cu rren tly n o reversible con traceptive th at all
wom en like an d are able to u se. A wom an m ay try
several m eth ods u n til sh e fin ds th e on e th at best
su its h er. Fu rth erm ore, a wom an m ay switch m eth -
ods several tim es du rin g h er reprodu ctive lifetim e
becau se of ch an ges in h er age, h ealth , econ om ic
secu rity, m arital statu s, lifestyle, an d con cept of ideal
fam ily size. All of th ese factors can h ave an im pact
on a wom an ’s decision s abou t con traception : wh en
to u se or stop u sin g it, wh at kin d to u se, an d wh en
to switch to an oth er m eth od. Even with Jadelle as an
option , th ere is a n eed for n ew con traceptives for
grou ps of wom en wh ose n eeds are n ot m et by avail-
able m eth ods.
65. Where was Jadelle tested?
Jadelle was stu died in th ree m u lticen ter trials begin -
n in g in 1990. Th e stu dies en rolled 1,393 rod u sers in
seven cou n tries. Alm ost h alf of th e wom en stu died
were in th e Un ited States; oth er clin ics were in Ch ile,
th e Dom in ican Repu blic, Egypt, Fin lan d, Sin gapore,
an d Th ailan d. Th e stu dies provided data on blood
levels, safety, an d efficacy.
Th e Cou n cil con du cted clin ical trials u sin g an
earlier version of th e rods in five cou n tries from
1983 to 1988. Th is version of th e rods h ad to be
reform u lated wh en an in gredien t in th e tu bin g was
discon tin u ed by th e m an u factu rer.
Mu ch of th e in form ation regardin g ch aracteris-
tics of levon orgestrel im plan ts com es from exten sive
stu dies of th e six-im plan t Norplan t. In addition ,
m an y cou n tries h ave con du cted prein trodu ction
stu dies to obtain data on local experien ce with th e
Norplan t m eth od an d to train providers in in sertion ,
rem oval, an d cou n selin g tech n iqu es. By 1991, wh en
th e m eth od becam e available in th e Un ited States,
Norplan t capsu les h ad been u sed in clin ical trials an d
prein trodu ction stu dies in volvin g over 55,000 vol-
u n teers in m ore th an 40 cou n tries.
66. Where has Jadelle been approved?
Regulatory agencies in the following countries have
approved Jadelle: Finland, France, Iceland, Indonesia,
Luxembourg, Netherlands, Norway, Spain, Sweden,
Thailand, and the United States.
67. Is there a risk of Jadelle being used coercively?
Th ere is a risk of an y provider-con trolled m eth od
bein g u sed coercively. Th e Popu lation Cou n cil
stron gly advocates th e volu n tary u se of an y con tra-
ceptive an d believes th at wom en h ave th e righ t to
balan ced an d accu rate in form ation , train ed an d
capable h ealth care providers, aseptic con dition s, an d
ability to discon tin u e th e u se of th e con traceptive on
requ est.
Wh erever provider-depen den t m eth ods are
offered, providers sh ou ld obtain wom en ’s in form ed
con sen t at th e tim e th e m eth od is adopted, an d u sers
sh ou ld h ave ready access to rem oval of th e rods by
com peten t h ealth care providers.
31
IN TERN ATION A L POSTMA RKETIN G SURVEILLA N CE
OF N ORPLA N T
A five-year in tern ation al postm arketin g su rveillan ce
of som e 8,000 Norplan t u sers in eigh t developin g
cou n tries com pared with th e sam e n u m ber of u sers
of eith er in trau terin e devices (IUDs) or sterilization
sh ows th e im plan ts to be a safe an d h igh ly effective
con traceptive m eth od (Meirik, Farley, an d Sivin
2001a; Meirik, Farley, Sivin et al. 2001b; Meirik,
Farley, Sivin et al. 2001c). Th e stu dy’s pu rpose was
to determ in e th e safety of th ese m eth ods in develop-
in g-cou n try settin gs an d to exam in e th e risk of rela-
tively rare pu blic h ealth even ts th at h ad n ot been
iden tified earlier in clin ical trials. Th e au th ors con -
clu ded th at Norplan t was n ot associated with an y
m aterial risk of m ajor m orbidity com pared with th e
two con trol grou ps. Th is stu dy was th e first prospec-
tive postregistration su rveillan ce of a n ewly in tro-
du ced con traceptive in developin g cou n tries.
Th e stu dy con clu ded th at all th ree m eth ods pro-
vided excellen t lon g-term protection again st
u n plan n ed pregn an cy an d con siderably redu ced th e
risk of ectopic pregn an cy. Average an n u al pregn an cy
rates for Norplan t, copper IUDs, an d sterilization
were less th an on e per 100 wom en . Con tin u ation
rates for both Norplan t an d IUDs averaged 90 per 100
wom en en terin g each year. Th e overall follow-u p
rate was 94.6 percen t; 78,323 wom an -years of obser-
vation were accu m u lated.
The study was conducted by the UNDP/UNFPA/
WHO/ World Ban k Special Program m e of Research ,
Developm en t an d Research Train in g in Hu m an
Reprodu ction (HRP), th e Popu lation Cou n cil, an d
Fam ily Health In tern ation al.
Workin g with in vestigators at 32 fam ily plan -
n in g clin ics in eigh t developin g cou n tries, th e su r-
veillance followed 7,977 Norplant capsule users, 6,625
users of IUDs, and 1,419 women who had been steril-
ized in Bangladesh, Chile, China, Colombia, Egypt,
Indonesia, Sri Lanka, and Thailand. With few excep-
tions, women were followed for five years, even if they
discontinu ed u se of th e m eth od, switch ed to an oth er
con traceptive, or becam e pregn an t. Th e wom en
m ade regu lar clin ic visits every six m on th s, reported
an y h ealth problem s, an d kept diaries of con tacts
with oth er h ealth providers an d facilities. Medical
32
records were obtain ed from clin ics an d h ospitals.
Wom en wh o h ad m issed a visit were con tacted.
Form er Norplan t u sers retu rn ed six weeks after
im plan t rem oval to en su re recordin g of an y rem oval
com plication s.
Clien ts were en rolled from 1987 to 1991, with
follow-u p com pleted in 1997. Nin ety-five percen t of
th e wom en en rolled in th e stu dy were accou n ted for
at th e en d of th e five-year follow-u p period.
All com plain ts, sym ptom s, an d diseases were
classified accordin g to th e In tern ation al Classification
of Diseases, 9th revision (ICD-9). All m ajor h ealth -
related even ts were reported an d reviewed. Major
h ealth even ts were poten tially life-th reaten in g prob-
lem s th at (a) requ ired h ospitalization , con valescen ce
of at least on e m on th , or m edication for th ree
m on th s or m ore, (b) resu lted in sequ elae, or (c) led
to death .
Majo r h e alth e ve n ts
Data were gen erally reassu rin g for m ajor h ealth
even ts. Th e stu dy reported n o sign ifican t excess of
m align an t n eoplastic disease or cardiovascu lar
even ts, su ch as stroke or ven ou s th rom boem bolism
in Norplan t u sers com pared to wom en u sin g n on -
h orm on al m eth ods. Fu rth erm ore, th e n u m ber of
su ch even ts was n ot greater th an th e expected esti-
m ate from popu lation -based in ciden ce rates. Th ere
was little or n o association between Norplan t u se
an d diabetes or th rom obocytopen ia. No association
was fou n d between Norplan t u se an d severe depres-
sion or severe con n ective tissu e diseases, su ch as sys-
tem ic lu pu s eryth em atosu s. Th e rates of diagn osis of
rh eu m atoid arth ritis an d polyarth ropath ies were low
an d n ot statistically sign ifican tly differen t between
Norplan t u sers an d wom en u sin g an IUD or th ose
sterilized.
Twen ty-two of 34 death s du rin g th e stu dy were
du e to acciden ts, su icides, an d h om icides. Th ere were
n o differen ces in th e n u m ber or pattern s of death s
accordin g to th e con traceptive m eth od ch osen .
Most oth er m ajor h ealth even ts reported in th e
stu dy w ere related to diseases of th e digestive an d
gen itou rin ary system s, reflectin g expected pattern s
of disease am on g oth erw ise h ealth y w om en of
reprodu ctive age in developin g cou n tries. Th e
research ers fou n d th at th e in ciden ce of gallbladder
disease w as m oderately h igh er in Norplan t u sers
com pared w ith w om en in th e con trol grou ps,
th ou gh th is occu rred m ain ly in u sers in Ch ile an d
Ch in a. Use of com bin ed oral con traceptives h as
been reported to be w eakly associated w ith gall-
ston e disease an d ch olecystitis in som e stu dies
(Th ijs an d Kn ipsch ild 1993). Wh ile th e overall in ci-
den ce of h yperten sion w as low in all con traceptive
grou ps, th e com bin ed in ciden ce of h yperten sion
an d borderlin e h yperten sion w as h igh er in cu rren t
Norplan t u sers com pared w ith w om en in th e con -
trol grou ps. Becau se Norplan t u sers h ad m ore fre-
qu en t blood pressu re m easu rem en ts, th e resu lts
m igh t partially reflect a reportin g bias, accordin g to
th e research ers. (A w om an w as classified as h avin g
h yperten sion if h er systolic blood pressu re w as
>140 m m Hg an d h er diastolic blood pressu re w as
>90 m m Hg on m ore th an on e occasion ; sh e w as
classified as h avin g borderlin e h yperten sion if th ese
resu lts w ere recorded on ly on ce.)
Pre gn an cie s
Th e m ajority of th e pregn an cies (1,134 ou t of 1,737)
occu rred am on g wom en wh o h ad stopped u sin g
con traception . Som e 317 wom en u sin g IUDs becam e
pregn an t; m ost of th ese were wom en in Ch in a u sin g
n on m edicated IUDs. An n u al pregn an cy rates du rin g
th e period of u se of Norplan t an d th e copper IUD an d
am on g sterilized wom en were less th an on e per 100
wom en . Eigh ty-n in e Norplan t u sers becam e preg-
n an t; ten of th ese pregn an cies were ectopic. Th e low
n u m ber of pregn an cies reflects th e m eth od’s h igh
effectiven ess.
Oth e r re p o rte d h e alth p ro ble m s
Th e stu dy con firm ed a h igh er in ciden ce of less seri-
ou s disorders previou sly described in Norplan t clin i-
cal trials an d/ or labelin g, su ch as irregu lar or exces-
sive m en stru al bleedin g, am en orrh ea, an d ovarian
cystic en largem en t n ot requ irin g h ospitalization . A
variety of sym ptom s an d con dition s, ran gin g from
h eadach es an d m ood ch an ges to respiratory tract
an d skin problem s, w ere also m ore frequ en tly
reported by wom en u sin g Norplan t th an by IUD
u sers an d sterilized wom en . However, th e h igh er
in ciden ce of th ese com plain ts by Norplan t u sers m ay
h ave been partly du e to th e fact th at th e im plan t was
a n ew m eth od for both service providers an d u sers,
leadin g to a greater focu s on h ealth problem s.
Clu sterin g of diagn oses also occu rred. For exam -
ple, cen ters in Colom bia, with 6.2 percen t of th e
stu dy’s participan ts, reported over 65 percen t of all
m igrain e h eadach es bu t on ly 1.6 percen t of oth er
h eadach es. Th is apparen t an om aly led research ers to
con clu de th at clin ician s in Colom bia did n ot u se th e
sam e diagn ostic sign s an d sym ptom s as were u sed
elsewh ere. In Ban gladesh , exten sive reportin g for
sterilization participan ts of oth er h ealth problem s,
su ch as h eadach e or m alaise, resu lted in h igh er over-
all in ciden ce rates for th ese con dition s th an fou n d
elsewh ere.
The researchers concluded that the postmarketing
surveillance demonstrated the feasibility of conduct-
ing large multicenter cohort studies in developing
countries and confirmed the safety with respect to
serious disease of Norplant, IUDs, and sterilization.
33
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