An Integrated Analysis of Nonmenstrual Adverse Events With Implanont
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
ORIGINAL RESEARCH ARTICLE
An Integrated Analysis of Nonmenstrual
Adverse Events With Implanont
J. Urbancsek
This integrated analysis evaluates nonmenstrual adverse gain.1 The percentage of progestin-only pill users
events, blood pressure, and body weight changes during reporting any nonmenstrual adverse events was gen-
the use of the single-rod etonogestrel-containing contracep- erally in the range of 21%– 45% whereas discontinu-
tive implant, Implanont; these aspects are compared for ation rates as a result of nonmenstrual adverse events
Implanon and Norplantt, the six-capsule implant contain- were ,10% in most studies.1,2
ing levonorgestrel. Overall, 47% of Implanon users had Users of the six-capsule levonorgestrel-containing
drug-related adverse events, whereas in the comparative implant, Norplantt, show considerable variations in
studies the figure for those using Implanon (61%) was the reported adverse events, both among populations
slightly lower than that for Norplant users (69%). In all
and among individuals.3,4 Headache, weight gain,
Implanon studies, 12 of 1716 women (0.7%) were affected
depression, anxiety, and mood changes are the most
by serious adverse events that were considered drug re-
commonly reported reasons for removal of Norplant,
lated. In comparative studies three of the 689 Implanon
but loss of libido, acne and other skin problems,
users (0.4%) and one of 689 Norplant users (0.1%) had such
breast tenderness, dizziness, and nausea are also fre-
experiences. The most frequently reported drug-related
quently reported.4,5
adverse events were acne, breast pain, headache, and
weight gain. The adverse events that most often caused
An integrated analysis of the safety data from 13
discontinuation of Implanon were weight gain and acne. studies of the single-rod etonogestrel-containing con-
The development or aggravation of acne was a frequent traceptive implant, Implanont, is reported. Evalua-
adverse event (in 18.5% of Implanon and 22.3% of Nor- tions of bleeding irregularities, dysmenorrhea, and
plant users in the comparative studies) but individual hemoglobin levels, as well as of implant insertion and
studies indicated that there were also many subjects removal, are not reported in this paper but are pub-
whose acne improved during implant use. There were lished in tandem with the present analysis.6,7 Aspects
gradual increases in body weight over time but these may be concerning the effects of Implanon on metabolic
only partly attributable to implant use and partly attribut- parameters, including hemostasis, lipid metabolism,
able to normal increases over time. CONTRACEPTION 1998;58: liver function, carbohydrate metabolism, and ophthal-
109S–115S © 1998 Elsevier Science Inc. All rights reserved. mology, will be considered in separate publications.
The aim of this analysis is to evaluate nonmen-
KEY WORDS: contraceptives, progestin-only, implant, etono- strual adverse events (AE), as well as Implanon’s effect
gestrel, adverse events, safety, Implanont on blood pressure and body weight, and to compare the
profile of Implanon with that of Norplant.
Introduction
Progestin-only contraceptives are associated with a
variety of adverse events, in addition to bleeding Materials and Methods
irregularities. The prevalence of headache, breast ten- Trials Included
derness, nausea, and dizziness may be slightly ele- The present analysis includes data from 13 different
vated with the use of these contraceptives. It has been clinical trials carried out in Europe, North and South
suggested that the androgenic activity of these con- America, and Southeast Asia between 1989 and 1997
traceptives may lead to acne, hirsutism, and weight (core data set; Table 1); six were open, noncompara-
tive trials, and seven were open, randomized, compar-
First Department of Obstetrics and Gynecology, Semmelweis University Medi- ative trials. In the comparative trials, the six-capsule
cal School, Budapest, Hungary levonorgestrel implant (Norplant) was used as the
Name and address for correspondence: Dr. J. Urbancsek, MD, PhD, Head,
Division of Assisted Reproduction, Department of Obstetrics and Gynaecology, reference product. The procedures described below
Semmelweis University Medical School, Baross Utca 27, H-1088 Budapest,
Hungary
and the definitions and methods used to record AE
NorplantT is a registered trademark of the Population Council, New York. were the same for all of the trials included.
© 1998 Elsevier Science Inc. All rights reserved. ISSN 0010-7824/98/$19.00
655 Avenue of the Americas, New York, NY 10010 PII S0010-7824(98)00122-X110S Urbancsek Contraception
1998;58:109S–115S
Table 1. Trials included in the core data set for the integrated analysis of adverse events
Implanon Norplant
Age Body weight Age Body weight
Trial no. Region N* (years)† (kg)† N* (years)† (kg)*
Comparative trials
34508 Europe 16 29.5 6 6.63 59.3 6 7.82 16 30.1 6 5.30 60.7 6 5.52
34509 Europe 43 28.2 6 5.88 60.5 6 7.62 43 28.4 6 5.58 60.2 6 7.04
34510‡ Indonesia (45) 29.3 6 3.65 49.8 6 8.35 (45) 31.7 6 4.71 54.5 6 8.16
34510 Thailand 15 28.5 6 5.37 51.3 6 6.77 15 27.7 6 5.47 51.4 6 4.79
34511 Singapore 40 29.1 6 4.61 58.1 6 11.1 40 29.2 6 3.88 56.5 6 8.26
34512 Europe 40 28.7 6 6.47 59.7 6 7.42 40 27.3 6 5.42 60.6 6 6.84
34514‡ Indonesia (11) 33.1 6 5.17 51.4 6 7.70 (10) 29.5 6 4.33 50.3 6 6.65
34514 Europe 30 27.0 6 4.71 63.8 6 6.82 30 26.1 6 4.49 61.1 6 7.34
34520‡ Indonesia (449) 29.0 6 5.04 49.6 6 8.37 (450) 29.5 6 5.24 50.0 6 8.31
Total comparative§ 184 184
(689) (689)
Noncomparative trials
34502 Thailand 15 26.0 6 5.37 52.7 6 6.76
34503§ Indonesia 15 29.7 6 2.26 46.7 6 6.33
34505 Thailand 100 26.3 6 4.79 51.2 6 7.05
34506§ Indonesia 200 28.3 6 3.74 49.8 6 8.12
34507§ Chile 107 28.6 6 5.47 59.3 6 6.61
34507 Europe 528 29.2 6 5.58 62.1 6 8.97
34507 Europe 52 24.0 6 4.15 63.1 6 10.1
34515 Singapore 10 32.3 6 4.52 56.0 6 7.77
Grand total§ 889 184
(1716) (689)
*Number of subjects in the ‘All-Subjects-Treated’ group, ie., those subjects who received study medication.
†Values are means 6 SD.
‡Studies in Indonesia and Chile (italics) differed substantially in reporting of adverse events from the other areas and these data have been considered
separately from the main data set (normal print).
§Figures without parentheses are the totals of women in studies excluding Indonesia and Chile; figures in parentheses are the totals of all studies.
Subjects plant consists of six capsules, each 3.4 cm long 3 2.4
All women enrolled in the trials were between 18 and mm in diameter and containing 36 mg levonorgestrel.
40 years of age, sexually active, and of childbearing Implanon was inserted using a disposable applicator
potential; they were in good mental and physical on the inside of the nondominant upper arm and
health, without contraindications to the use of con- Norplant was inserted according to the manufactur-
traceptive steroids, had regular menstrual cycles, and er’s instructions. The implants were initially in-
were willing to give written informed consent. tended to be left in place for 2 years but volunteers
were given the opportunity to extend this to 3 years
(and in some cases up to 5 years). Volunteers using
Procedures
Norplant could continue beyond the study period
At the screening visit, subjects who complied with all
because the contraceptive effects of this system are
of the inclusion and exclusion criteria underwent a
claimed to last for 5 years. All volunteers were asked
general medical and gynecologic examination and
to attend the clinic regularly and whenever a serious
their medical, gynecologic, and drug histories were
complaint occurred during the studies.
obtained. In addition, a cervical smear was collected,
hemoglobin was measured, and a pregnancy test was
done. The cervical smear result had to be Papanico- Subject Assessment
laou class I or II for the women to be included in the Subjects were to visit the trial clinics at least once
study. If the results of these assessments were satis- every 3 months. At each visit the implantation site
factory, Implanon was inserted on or between days 1 was inspected, diary cards were checked and col-
and 5 of a menstrual period, or Norplant was inserted lected, and possible signs of pregnancy, occurrence of
on or between days 1 and 7. adverse events, and use of concomitant medication
Implanon, a single-rod implant, is 4 cm long 3 2 were assessed by open questioning. Blood pressure
mm diameter and contains 68 mg etonogestrel (the and body weight were measured at implant insertion,
biologically active metabolite of desogestrel). Nor- after 3 and 6 months, and every 6 months thereafter.Contraception Nonmenstrual Adverse Events With ImplanonT 111S
1998;58:109S–115S
Once a year, subjects also underwent a pelvic and lows. A systolic blood pressure recording that was
physical examination. Cervical smears were taken at .140 mm Hg and had increased .20 mm Hg from
screening and at the end of the study. All adverse baseline at at least two assessments or at last assess-
events were recorded according to terminology de- ment (single recording) was considered clinically sig-
fined by the World Health Organization (WHO). nificant. A clinically significant diastolic blood pres-
sure had to read .90 mm Hg and increase .10 mm
Integrated Analysis of Adverse Events Hg from baseline at at least two assessments or at last
From the data collected in individual studies, it was assessment. An increase in body weight of .10%
clear that there were regional differences in the re- from baseline at least once during treatment was
porting of AE. Therefore, a preliminary analysis of considered clinically significant.
these differences has been performed to determine
whether data from any region should be excluded
Statistical Analysis
from the main data set.
The frequencies of AE with Implanon and Norplant
Data are presented for two populations: 1) all Impla-
were compared using x2 tests. For vital signs, compar-
non users in all studies (noncomparative and compar-
isons of changes from baseline were done using the
ative); and 2) Implanon and Norplant users in the
center-adjusted Cochran-Mantel-Haenszel test.
comparative studies. Data for IUD users, who were
included in one study, are not presented.
Adverse events are defined as any new complaint or Results
symptom emerging during the study period or any
Study Population
preexisting complaint or symptom that increased in
Details of the study populations included in the
severity or frequency during the study period; severe
analysis are shown in Table 1; the populations ex-
AE are those that interfere significantly with func-
posed to both systems in comparative trials were
tioning. Serious adverse events (SAE) include those
similar with respect to age and body weight. The
that are fatal, life-threatening, permanently disabling,
preliminary AE analysis indicated that there were no
require inpatient hospitalization, or prolong hospital-
consistent differences between countries except that
ization, and include congenital anomalies, cancer,
far fewer AE were reported in Indonesia and many
and overdose. The numbers and percentages of sub-
more in Chile than in the other regions. This low
jects with AE, SAE, discontinuation due to AE, AE of
incidence was seen in both treatment groups in the
severe intensity, and drug-related AE (judged by the
large comparative study (study 34520) conducted in
investigator) are presented. The drug-relatedness of
Indonesia. The Indonesian sites contribute to more
SAE was judged both by the investigator and by
than 40% of the subjects for all studies, whereas for
Organon’s SAE committee. In case of a difference in
the comparative studies the Indonesian contribution
opinion, the most serious (closest) relationship is
is more than 70%. The number of subjects participat-
presented. The SAE that were thought to be possibly,
ing in the Chilean centers is limited compared with
probably, or definitely related to study drug adminis-
Indonesia (about 6% of the total study population).
tration were classified as drug-related and those that
Pooling the data of these deviating centers with the
were thought to be unlikely or not related were
data of all other studies would lead to heterogeneity
classed as not related.
in the data and hinder the interpretation of all AE data.
Women who discontinued treatment, giving AE as
The results for the other countries are presented to-
the primary reason, are listed. In some studies only
gether (main data set) and those for Indonesia and Chile
one AE was specified as the most important AE
are presented separately. The total extent of exposure
leading to discontinuation. In these cases only the
(all studies, all regions) was 4103 woman-years for
marked AE is listed; for the other studies, all AE
Implanon and 1826 woman-years for Norplant.
mentioned as leading to discontinuation are listed.
Adverse Events
Acne
There were no deaths reported among the study
In four studies (34507, 34509, 34512, 34515), acne
populations. Table 2 summarizes the frequencies of AE.
intensity was assessed both before implant insertion
In total, 61 SAE have been reported with Implanon
and at removal.
(all regions combined). Overall, 12 of 1716 (0.7%)
women receiving Implanon had SAE that were con-
Blood Pressures and Body Weights sidered to be possibly or probably drug related. None
Criteria for the identification of clinically signifi- of the SAE were considered to be definitely drug-
cantly abnormal vital signs were predefined as fol- related in either group. In the comparative studies,112S Urbancsek Contraception
1998;58:109S–115S
Table 2. Frequencies of adverse events for all Implanon studies and for comparative studies
No. (%) of women reporting adverse event
Comparative studies
All studies
Implanon Implanon Norplant
Main data set
No. of women included 889 184 184
Serious adverse events* 54 (6.1) 7 (3.8) 5 (2.7)
Drug-related serious adverse events* 12 (1.3) 3 (1.6) 1 (0.5)
Adverse events* 638 (71.8) 150 (81.5) 163 (88.6)
Adverse events of severe intensity* 90 (10.1) 19 (10.3) 21 (11.4)
Drug-related adverse events* 421 (47.4) 112 (60.9) 127 (69.0)
Adverse events causing discontinuation 65 (7.3) 11 (6.0) 14 (7.6)
Chile
No. of women included 107
Serious adverse events* 7 (6.5)
Drug-related serious adverse events* 0
Adverse events* 106 (99.1)
Adverse events of severe intensity* 31 (28.9)
Drug-related adverse events* 97 (90.7)
Adverse events causing discontinuation 16 (15.0)
Indonesia
No. of women included 720 505 505
Serious adverse events* 0 0 0
Adverse events* 35 (4.9) 21 (4.2) 28 (5.5)
Adverse events of severe intensity* 0 0 2 (0.4)
Drug-related adverse events* 12 (1.7) 9 (1.8) 14 (2.8)
Adverse events causing discontinuation 7 (1.0) 4 (0.8) 5 (1.0)
*For definitions see ‘‘Integrated analysis of adverse events’’ in the Materials and Methods section.
seven SAE were reported with Implanon and five with The overall incidence of AE in Implanon studies
Norplant. Three of 689 (0.4%) women using Impla- was 72% (main data set; Table 2), whereas in
non had SAE that were considered drug related; in the comparative studies the incidences were 82% for
Norplant group there was one of 689 (0.1%) women Implanon and 87% for Norplant. The corresponding
with a drug-related SAE—an ovarian cyst—which is a figures for Implanon for Chile (noncomparative
known complication of progestin-only administration. studies only) and Indonesia (comparative as well as
The 12 drug-related SAE with Implanon (including noncomparative studies) were 99% and 5%, respec-
the seven that were reported in the comparative studies) tively.
are presented here. A case of papilloma (Condyloma In all of the Implanon studies (main data set), 47%
vulvae) was judged as drug-related because it was prob- of women reported AE that were considered to be
ably caused by a human papillomavirus infection, the drug related (Table 2). In comparative studies, drug-
expression of which could have been induced by the
related AE occurred in a smaller proportion of those
administration of steroid hormones. One subject was
using Implanon (61%) than in those using Norplant
initially diagnosed as having a transient ischemic attack
(69%), although the difference was not statistically
(TIA) but this diagnosis could not be substantiated by
significant (p 5 0.170).
magnetic resonance imaging and computerized tomog-
In all of the Implanon studies, the drug-related AE
raphy. Nevertheless, this was listed as a drug-related
SAE. One subject developed chest pain/tachycardia, that occurred most frequently (in .5% of subjects in
which was first noticed a half day after implant one of the treatment groups in comparative studies in
insertion. The symptoms worsened over the next 3 the main data set; Table 3) were acne (15.3%), breast
days and the implant was, therefore, removed. Symp- pain (9.1%), headache (8.5%), and weight increase
toms remained for at least another week. As the (6.4%). These AE were similar for the two treatment
half-life of elimination of etonogestrel is about 24 h, a groups although the percentages of patients affected
drug relationship becomes doubtful. Nine other SAE were slightly higher, albeit not significantly (p .0.05),
in Implanon users that were considered to be drug in the Norplant group (Table 3). In Chilean implant
related were: breast fibroadenosis (n 5 2), headache, users the most frequently observed AE were similar
uterine fibroid, ovarian cyst, cervical dysplasia, fever/ to those seen in the other regions, although they were
headache, teratoma, and asthma. seen in considerably greater percentages of patientsContraception Nonmenstrual Adverse Events With ImplanonT 113S
1998;58:109S–115S
Table 3. Drug-related adverse events with incidences of $5% (for Implanon or Norplant in comparative studies)*
Percentage of women reporting adverse event
Implanon, Implanon Norplant, Implanon,
all studies† comparative† comparative† Chile
(N 5 889) (N 5 184) (N 5 184) (N 5 107)
Adverse event Drug related Total Drug related Total Drug related Total Drug related Total
Acne 15.3 16.1 18.5 18.5 21.2 22.3 11.2 11.2
Breast pain 9.1 10.6 9.8 9.8 11.4 12.5 24.3 29.9
Headache 8.5 12.9 16.8 21.2 20.1 28.3 54.2 69.2
Weight increase 6.4 7.1 6.5 6.5 7.1 7.1 38.3 40.2
Abdominal pain 4.3 8.1 8.2 11.4 8.2 9.8 21.5 42.1
Libido decrease 2.9 3.0 3.3 3.3 5.4 5.4 15.9 17.8
Dizziness 2.9 4.3 6.5 8.7 7.1 8.7 13.1 16.8
Injection site pain 2.6 2.8 4.9 4.9 7.1 7.1 15.9 16.8
Emotional lability 2.5 2.7 4.9 5.4 7.6 7.6 0.0 1.9
Influenza-like symptoms 2.1 6.9 7.1 10.9 4.3 13.6 0 18.7
Nausea 2.0 3.6 3.3 3.8 5.4 6.5 3.7 10.3
*There were no drug-related adverse events with incidences of $5% in the Indonesian subjects.
†The main data set includes data for Europe, Thailand, Singapore, and Canada.
(Table 3). No individual AE affected as many as 5% of tion in all of the Implanon studies were weight gain
women in the Indonesian studies. and acne. In the comparative studies the reasons for
Adverse events of severe intensity were experienced discontinuation were not distinctly different between
by 10.1% of Implanon users in all studies (main data the two implants (Table 4).
set). In comparative studies, severe AE were experi-
enced by 10.3% of Implanon users and 11.4% of Nor-
plant users. In Chile and Indonesia these incidences Acne
were 29.0% and 0.0%, respectively, for Implanon users. Acne had the highest incidence of all drug-related AE
in both systems (Table 3).
Discontinuations Due to Adverse Events Other Table 5 shows the shifts from baseline to implant
Than Bleeding Irregularities removal for acne. Acne was present in 24% of the
Overall, 7.3% of Implanon users (main data set) women at baseline, and in 21% of the women at
discontinued use, giving an AE other than bleeding removal. In 108 of 184 of the women with preexisting
irregularities as the primary reason. In comparative acne (59%), this condition disappeared or improved
studies, the figures were 6.0% for Implanon and 7.6% (light gray area). In 18 of 184 women (10%), the
for Norplant, whereas in Chile and Indonesia the condition worsened during treatment and 83 of 576
figures were 15% and 1%, respectively (Table 2). The women unaffected at baseline developed acne (14%)
most frequently occurring reasons for discontinua- (dark gray area).
Table 4. Adverse events reported as the primary reason for discontinuation in $1% of any of the study populations*
No. (%) of women discontinuing
Main data set† Chile, all
all studies Main data set† comparative studies studies
Implanon Implanon Norplant Implanon
Adverse event (N 5 889) (N 5 184) (N 5 184) (N 5 107)
Weight increase 13 (1.5) 1 (0.5) 1 (0.5) 6 (5.6)
Acne 9 (1.0) 2 (1.1) 3 (1.6) 1 (0.9)
Decreased libido 6 (0.7) 2 (1.1) 1 (0.5) 0 (0.0)
Depression 4 (0.4) 2 (1.1) 3 (1.6) 0 (0.0)
Headache 3 (0.3) 0 (0.0) 1 (0.5) 5 (4.7)
Dizziness 0 (0.0) 0 (0.0) 1 (0.5) 2 (1.9)
*There were no adverse events reported as the primary reason for discontinuation in $1% of the study population in the Indonesian subjects.
†The main data set includes data for Europe, Thailand, Singapore, and Canada.114S Urbancsek Contraception
1998;58:109S–115S
Table 5. Acne intensity, shift from screening to last measurement (studies 34507, 34509, 34512, 34515)
Acne at last measurement
Total None Occasional Mild Severe
Acne at
screening N % N % N % N % N %
None 576 75.8 493 64.9 46 6.1 36 4.7 1 0.1
Occasional 139 18.3 84 11.1 39 5.1 13 1.7 3 0.4
Mild 45 5.9 21 2.8 3 0.4 19 2.5 2 0.3
Total 760 100 598 78.7 88 11.6 68 8.9 6 1.4
The figures were similar to those reported in com- ache, and body weight increase were the most fre-
parative studies (Implanon, n 5 82; Norplant n 5 80) quent drug-related AE among Implanon users,
with both treatments. whereas the AE that most often caused discontinua-
tion of Implanon were acne and body weight increase.
With Norplant, similar incidences were reported.
Blood Pressure
The events defined as drug related included all
The incidence of clinically significant increases in
those that were thought by the investigator to be
blood pressure was low. In all studies, among the
1710 evaluable Implanon users, seven (0.4%) had possibly or probably related to the study drug. This
clinically significantly increased systolic and 12 inevitably includes events that are not related to
(0.7%) had clinically significantly increased diastolic implant use but occur frequently in the study popu-
pressure values. In comparative studies, the corre- lation in any case. In the present analysis, most of the
sponding figures were one woman (0.1%, systolic) and events recorded as drug related have previously been
three women (0.4%, diastolic), of 688 using Implanon, associated with the use of progestin-only contracep-
whereas for Norplant there were six systolic (0.9%) tives, indicating that they could be drug related (with
and five diastolic (0.7%), of 687 women. The median the possible exception of influenza-like symptoms).
systolic and diastolic blood pressures were unchanged Large regional differences in both the levels and
in both treatment groups. distribution of AE have been seen in previous studies
with Norplant.3,4 Similar regional differences were
noted in the present study for both implant systems,
Body Weight particularly in Chile and Indonesia. Such differences
Weight increase was reported as a drug-related AE in are probably the result of cultural, social, and envi-
6.4% of all Implanon users (Table 3), whereas in ronmental differences but differences in the basic
comparative studies it was reported by a similar rates of symptoms and in the interpretation of proto-
proportion of Norplant users (7.1%). Clinically signif- cols may also contribute.
icant increases in body weight (.10% more than The AE seen most frequently in the present study
baseline) were seen in 20.7% of all Implanon users. were typical of the spectrum of adverse events seen
The incidence observed in the comparative studies with progestin-only contraceptives in general1 and
was 21.0% for Implanon and 17.6% for Norplant. A were similar to those previously reported in studies
gradual mean increase in body weight over time, with Norplant.4,5,8 –10
amounting to 1.5%–2% per year, was noted for both Acne was frequently reported as an adverse event
implant systems. In one comparative study (study with both implants. However, in the Implanon stud-
34510, based on Indonesian data only), nonmedicated ies in which acne was observed more thoroughly, it
IUD users were included. Mean body weight in- was found that the incidences of acne were similar at
creases were 2.6%, 2.9%, and 2.4% over 2 years for baseline and at removal. In women with acne at
Implanon, Norplant, and IUD users, respectively. baseline the condition improved in the majority of
women, whereas it first occurred in 14% or worsened
Discussion in 10%. In comparative studies with both systems, a
Overall, 47% of Implanon users (main data set ex- similar pattern was seen. This suggests that acne
cluding Indonesia and Chile) had drug-related non- presents less of a problem for implant users than the
menstrual AE at any time during their 2–5 years’ AE data indicate, and illustrates the negative bias that
participation in the studies. In the comparative stud- may be introduced by presenting only AE and no
ies, the figures for Implanon and Norplant users were improvement of preexisting conditions.
61% and 69%, respectively. Acne, breast pain, head- Small but steady weight increases were noted forContraception Nonmenstrual Adverse Events With ImplanonT 115S
1998;58:109S–115S
both Implanon users and Norplant users. However, in 2. WHO Task Force on Oral Contraceptives. A randomized
the comparative study that included a reference group double-blind study of two combined and two progestogen-
of IUD users, the body weight increase after 24 only contraceptives. Contraception 1982;25:243–52.
3. Grubb GS, Moore D, Anderson NG. Pre-introductory
months for IUD users was 2.4%, compared with 2.6 clinical trials of Norplant® implants: a comparison of
and 2.9% for Implanon and Norplant, respectively. seventeen countries’ experience. Contraception 1995;
These data indicate that the body weight increases 52:287–96.
noted in implant users are largely attributed to a 4. Sivin I, Viegas O, Campodonico I, et al. Clinical
normal increase over time and are therefore only performance of a new two-rod levonorgestrel contra-
partly attributable to implant use. ceptive implant: a three-year randomized study with
Norplant® implants as controls. Contraception 1997;
Nonmenstrual AE were generally of minor im-
55:73– 80.
portance and incidence. None of the SAE was 5. Lapido O, Coutinho EM. Contraceptive implants. Curr
definitely attributable to Implanon use. In compar- Opin Obstet Gynecol 1994;6:564 –9.
ative studies, both the frequencies and the nature of 6. Affandi B. An integrated analysis of vaginal bleeding
the nonmenstrual AE seen were similar for Im- patterns in clinical trials of Implanon®. Contraception
planon and for Norplant users. Detailed analysis 1998;58(suppl):99S–107S.
showed acne not to be a problem in the users of 7. Mascarenhas L. Insertion and removal of Implanon®.
Contraception 1998;58(suppl):79S– 83S.
progestin-only implants. Body weight tended to
8. Sivin I. Contraception with Norplant® implants. Hum
increase over time, but this was attributed mainly Reprod 1994;9:1818 –26.
to normal increases over time. 9. Davies GC, Newton JR. Subdermal contraceptive im-
plants—a review: with special reference to Norplant.
References Br J Fam Plann 1991;17:4 – 8.
1. McCann MF, Potter LS. Progestin-only oral contracep- 10. Sivin I. International experience with Norplant® and
tion: a contraceptive review. X. Common side effects. Norplant-II contraceptives. Stud Fam Plann 1988;19:
Contraception 1994;50:S11–38. 81–95.You can also read
