Obstetrics/Gynecology

Implanon: A Critical Review

Jennifer Le and Candy Tsourounis

OBJECTIVE: To evaluate clinical information on Implanon as a long-term method of contraception and, specifically, to review the
efficacy and adverse effect profile of Implanon.
DATA SOURCES: A MEDLINE search (from 1966 through June 1999) was performed to retrieve primary and review articles. The
search was limited to data on human subjects. Some references were identified through secondary sources.
STUDY SELECTION AND DATA EXTRACTION: Pharmacokinetic and pharmacodynamic studies, and clinical trials assessing the efficacy
and safety of desogestrel implants were reviewed. Relevancy and consistency of information was assessed for each trial.
DATA SYNTHESIS: Implanon is the newest contraceptive implant system that has completed worldwide Phase III clinical trials. It is a
single rod that contains a core of 68 mg of 3-keto-desogestrel with a membrane of ethylene vinyl acetate. Inhibition of ovulation
occurs within one day of implantation, and effective contraception lasts for three years. Fertility returns within one month after
implant removal. Insertion and removal by trained medical professionals is simple, and only minor complications have been
documented. Adverse effects are mild and primarily consist of abnormal bleeding, weight gain, acne, breast pain, and headache.
CONCLUSIONS: The data on Implanon indicate that it provides effective long-term contraception with limited adverse effects. It
appears to be a good addition to the currently available contraceptives.
KEY WORDS: contraception, Implanon, 3-keto-desogestrel, etonorgestrel.

Ann Pharmacother 2001;35:329-36.

ACPE UNIVERSAL PROGRAM NUMBER: 407-000-01-009-H01

revention of unintended pregnancy through contracep-
P tion is critical for family planning as well as in elimi-
nating the need for high-risk abortions and deaths from re-
lated complications. This is especially important in the
adolescent population.1,2 Long-acting implantable methods
of contraception, such as Norplant, are cost-effective when
compared with the cost of unplanned pregnancy.3,4 The
search for effective contraceptive methods is targeted at re-
ducing costs and risks associated with abortions and preg-
nancy. Implants offer the most effective contraception,
with an expected and typical failure rate of 0.035% (Table
1).5 This is eight times less than the expected rate of acci-
dental pregnancy and 85 times less than the failure rate of
oral contraceptives. One reason for the success of long-act-
Author information provided at the end of the text.
Implanon (desogestrel, Organon International BV, West Orange,
NJ).
ing implants is that compliance is not a concern, unlike
with oral contraceptives and condoms. Contraceptive im-
plants are associated with a high, one-year continuation
rate,6 and are also more cost-effective compared with oral
contraceptives.3,6
Natural progestins are released by the corpus luteum
and stimulate endometrial progression from the follicular
to the secretory phase. Synthetic compounds are being de-
veloped with reduced androgenic activity and increased
potency. The benefits of progestin-only implants include a
long duration of action, short fertility recovery time after
removal, protection against endometrial and ovarian can-
cer, and decreased incidence of pelvic inflammatory dis-
ease and vulvovaginal candidiasis.7 One of the most useful
roles for progestin-only implants is in situations where ex-
ogenous estrogens are contraindicated. Norplant, the cur-
rently available implant, contains a progestin within a sus-
tained-release system that delivers therapeutic concentra-

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J Le and C Tsourounis
tions of levonorgestrel for several years. Implanon is the
newest implant system that has completed worldwide
Phase III clinical trials as a long-term method of contra-
ception. The following is a review of Implanon and its role
in contraception.
Pharmacology
Implanon releases 3-keto-desogestrel (3-KDSG), which is
a progesterone metabolite (MW 324.44). This active metab-
olite inhibits ovulation by altering the hypothalamic–pitu-
itary– ovarian (HPO) control mechanism. 3-KDSG achieves
supraphysiologic concentrations, resulting in negative feed-
back on the HPO axis and the down-regulation of luteiniz-
ing hormone (LH) surge.8 The LH surge is required to sup-
port the production, growth, and maturation of ovarian fol-
licles. In addition, the implant also hinders conception by
preventing implantation through inhibition of endometrial
proliferation.9 Hindering sperm migration by increasing
viscosity of cervical mucus also serves to improve contra-
ceptive efficacy, particularly in the third year after implan-
tation when ovulation resumes in 4% of patients.8,10
Receptor binding studies11 have demonstrated that 3-
KDSG has high progestational activity and low intrinsic
androgenicity. The quick rise to plateau serum concentra-
tion of 3-KDSG facilitates anovulation within one day af-
ter insertion. Some ovarian activity may remain intact as
evidenced by the appearance of the follicular phase in the
presence of high estrogen concentrations.10,12
Pharmacokinetics
ABSORPTION AND DISTRIBUTION
In vitro studies13,14 have demonstrated that the Implanon
system releases 3-KDSG at a rate of 60 –70 µg/d within
the first four weeks after implantation, followed by 40, 34,
Table 1. Lowest Expected and Typical Failure Rates
During the First Year of Use of Contraceptive Method5,a
Method Lowest Expected (%)b Typical (%)c
Oral contraceptives 0.3
Diaphragm with spermicidal 6 18
cream or jelly
Intrauterine devices 2 3
Implants (capsules and rods) 0.035
Condom without spermicide 2 12
Female sterilization 0.2
Male sterilization 0.1
No contraception (planned 85
pregnancy)
a
Adapted with permission.
b
Represents the percentage of women expected to experience an ac-
cidental pregnancy.
c
Represents actual percentage of women who experienced an acci-
dental pregnancy.
330 ■ The Annals of Pharmacotherapy ■ 2001 March, Volume 35
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and 25–30 µg/d at the end of the first, second, and third
years, respectively. In vivo, the absorption rate reaches 60
µg/d after three months and slowly declines to 30 µg/d af-
ter two years.15 The bioavailability of 3-KDSG remains
nearly 100% throughout three years.14
Inhibition of ovulation occurs within one day of inser-
tion.13 After eight hours, the mean serum concentration
reaches 266 pg/mL (>90 pg/mL indicates anovulation).9
The maximum serum concentration of 813 pg/mL attained
on day 4 is followed by a decline to a mean concentration
of 176–196 pg/mL after the first year.9,12,14 The concentra-
tion continues to gradually decrease during the second and
third years, reaching 156 pg/mL at the end of the third
year.14 Women who weigh <50 kg appear to have signifi-
cantly higher serum concentrations of 3-KDSG.9
METABOLISM AND ELIMINATION
Desogestrel implants do not undergo hepatic first-pass
metabolism. The active metabolite (3-KDSG) primarily
binds to albumin.9 The half-life of 3-KDSG is 25 hours.
The clearance remains constant at 7.5 L/h, and there is no
evidence of accumulation.15 The route of elimination is un-
known. Upon removal of the implant, 3-KDSG decreases
to undetectable concentrations (<20 pg/mL) within one
week.14 Return of ovulation is established in 94% of pa-
tients within three weeks, but may extend to six weeks.8,9,10
In one trial,16 91% of patients resumed normal menses
within three months of implant removal.
Clinical Trials
The first clinical trial12 conducted with desogestrel im-
plants evaluated the steroid release rate and plasma con-
centrations required to prevent conception. In this open-la-
bel, two-year trial, implants were inserted in 30 women
with regular menstrual cycles. The control group consisted
of 25 women using intrauterine devices. Implant release
rates ranged from 10 to 40 µg/d. All women received vary-
ing doses until the implants were discontinued because of
pregnancy or detection of ovulation. The implants were
placed in the anterior aspect of the nondominant arm.
All women were between 18 and 35 years of age, were
fertile, and had no underlying medical conditions. Subjects
3
were excluded if they had contraindications to steroids,
were actively breast feeding, had pelvic inflammatory dis-
ease since last pregnancy, or had received an injectable
0.035
contraceptive in the previous year. Progesterone, estradiol,
3-KDSG, and lipoproteins were measured on a regular ba-
0.4
sis; daily recordings of bleeding events were completed by
0.15
all women. Women who experienced delayed menses of
85
≥15 days were given urinary pregnancy tests. Confirma-
tion of pregnancy was performed by immunologic detec-
tion of HCG and ultrasound. Ovulation was confirmed
when progesterone concentrations were >9.5 nmol/L.12
Inhibition of ovulation occurred in 97% of cases where
the implants released 3-KDSG at a rate of 40 µg/d and
achieved serum concentrations >280 pg/mL. Release rates
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<40 µg/d did not achieve adequate inhibition of ovulation.
Progesterone concentrations consistent with ovulation
were detected in approximately 50% of the sampling peri-
ods that had plasma concentrations of 3-KDSG ≤280
pg/mL. Efficacy was low in patients who received doses
below the threshold release rate and plasma concentration.
Three pregnancies occurred in patients with implants de-
livering ≤20 µg/d of 3-KDSG. Detection of estradiol con-
centrations, which were significantly higher in the treat-
ment group than the control group (p < 0.05), suggested
that ovarian activity was not inhibited. Follicular function
remained active. Follicular cysts were confirmed in 22%
of the patients by pelvic examination and ultrasound.
These masses (35–65 mm) disappeared within seven to 90
days. No significant changes in cholesterol, high-density
lipoprotein-cholesterol, and triglycerides were detected.12
At week 12 of the study, one woman had suspected sub-
clinical viral hepatitis. This was evident by elevated aspar-
tate aminotransferase, lactic dehydrogenase, and alkaline
phosphatase concentrations, all of which resolved within
two weeks. Three cases of cutaneous allergy were ob-
served, one of which led to premature discontinuation. In
the initial months, implant use resulted in an increase in
bleeding days (>15) and spotting days as well as bleeding
episodes (>3) per 90-day interval. Bleeding irregularities
did not require implant removal. Increased weight (n = 3
subjects), follicular cysts (2), headaches (1), general dis-
comfort (1), and cutaneous allergy (1) resulted in prema-
ture study withdrawals. No pregnancies occurred in wom-
en who received at least 40 µg/d of 3-KDSG. Ten patients
received extra contraception (Copper T or spermicides)
due to evidence of luteal activity, an indicator of fertility.12
In a prospective, randomized, multicenter trial, Maka-
rainen et al.9 conducted a comparison between Implanon
and Norplant. The study assessed the effects of Implanon
on ovarian function for two years in Sweden and three
years in Finland. The products used in the trial were Impla-
non, a single rod system composed of 68 mg of 3-KDSG,
and Norplant, a system of six Silastic capsules, each con-
taining 36 mg of levonorgestrel. The implants were insert-
ed within the first five days of the menstrual cycle in 32
healthy, fertile women who were between 18 and 40 years
of age (mean 30). Sixteen women received Implanon and
the other 16, Norplant. All women had confirmed normal
ovulatory cycles (mean length 28 d) and total body weight
between 80% and 120% of ideal body weight (mean weight
60 kg). Ovarian function and endometrial thickness were
assessed by ultrasonography. In addition, blood samples
were assayed for 3-KDSG or levonorgestrel, progesterone,
17β-estradiol, and sex-hormone- binding globulin (SHBG)
at regular intervals. Daily recording of bleeding events or
other adverse experiences, physical and gynecologic ex-
aminations, Papanicolaou (Pap) smear, and vital signs were
monitored.
Patients receiving Implanon achieved effective contra-
ception within eight hours, which was maintained for three
years. There were no pregnancies in either treatment group.
Maximum serum concentrations of 3-KDSG and levo-
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Implanon: A Critical Review
norgestrel were achieved on day 4 and day 20, respective-
ly. The maximum serum concentrations achieved with
Norplant showed a greater variability between patients
than that achieved with Implanon. Inhibition of ovulation
was first observed after 30 months with Implanon and 18
months with Norplant in all patients except in two users of
Implanon and one of Norplant. Ovulation in these three
women was confirmed by a progesterone concentration of
≥16 nmol/L. Ultrasonograph confirmed ovulation in the
two Implanon users. One of the two Implanon users had a
3-KDSG serum concentration decrease to 120 pg/mL at
the time of ovulation, indicating variation in the effective
serum concentration of 3-KDSG between individuals. A
previous study12 suggested that inhibition of ovulation re-
quired 3-KDSG concentrations >90 pg/mL.
After implant removal, serum concentrations of 3-KDSG
decreased to <20 pg/mL within seven days. Serum con-
centrations of levonorgestrel decreased to 40 pg/mL after
two weeks. Return of ovulation within six weeks was es-
tablished in all patients who finished the study. Both treat-
ment groups experienced a similar decline in estradiol con-
centration to a range consistent with the early follicular
phase. Any elevation in estradiol concentration during
treatment was indicative of follicular development.9 Long-
term hypoestrogenism and hyperestrogenism were not ob-
served in either group, despite the changes in estradiol con-
centration.9
Throughout the study, patients in the Norplant group
had higher estradiol concentrations, which may correlate
with the higher occurrence of follicular cysts among these
patients. Subjects with follicular cysts >30 mm were
asymptomatic. These cysts spontaneously disappeared in
both treatment groups, except in one Norplant user who re-
quired cystic puncture. In addition, both groups experi-
enced endometrial thinning, which may have enhanced
contraceptive activity. The decrease in endometrial thick-
ness was more uniform in subjects using Implanon. Serum
concentrations of SHBG decreased in both groups; Nor-
plant users showed a greater decline of 25.7%. This may
be related to a higher intrinsic androgencity associated
with levonorgestrel. 3-KDSG binds preferentially to albu-
min and levonorgestrel binds to SHBG. As a result, serum
concentrations of 3-KDSG were more predictable and
fluctuated less.9
The cervical smear of Papanicolaou class I or II re-
mained unchanged before and after treatment. Systolic and
diastolic blood pressures decreased from baseline in both
groups. Many patients experienced an average weight in-
crease of 1.6 kg with Implanon and 1.3 kg with Norplant.
Other adverse effects related to implant use were depres-
sion, which was reported in two Norplant users. Changes
in vaginal bleeding patterns also occurred and varied
among implant users. Infrequent bleeding (defined as <3
bleeding or spotting events per 90-d period) occurred
more frequently in patients using Implanon (53.3%) than
in those using Norplant (18.8%).9 Previous results14 sug-
gested Norplant had a 41.1% incidence of infrequent
bleeding. Amenorrhea was reported only in three subjects
The Annals of Pharmacotherapy ■ 2001 March, Volume 35 ■ 331
J Le and C Tsourounis

who used Implanon. Amenorrhea occurred in the absence tachycardia with chest pressure, were judged possibly
of estradiol peak concentrations, regardless of estradiol drug-related. Physical and pelvic examinations were unre-
concentration. In contrast, withdrawal bleeding within markable. The average times for insertion and removal
three to five days was usually preceded by an estradiol were 2.2 and 5.4 minutes, respectively. Complications re-
peak. Bleeding irregularities accounted for the majority of lated to insertion and removal were rare (1.3–3.0%). Most
early discontinuations. Overall, 37.5% of Implanon pa- patients (96.2%) did not report swelling, redness, pain, or
tients and 12.5% of Norplant users discontinued therapy hematoma at the implant site during treatment. The return
due to altered bleeding patterns. One subject in the Nor- to normal menses occurred in 90.9% of patients within
plant group who experienced depression also abandoned three months.16
treatment. The number of patients who completed the
study in the Implanon and Norplant groups was nine and Adverse Effects
11, respectively, in Sweden (2 y); and seven and three, re-
spectively, in Finland (3 y). Insertion and removal of the The adverse effects associated with desogestrel implants
implants were uncomplicated in all cases except in one include menstrual irregularity, weight gain, acne, breast
with Norplant. The average time for implant removal was pain, headache, and temporary infertility after discontinua-
significantly less in Implanon users (5.9 min) than Nor- tion (Table 2). In clinical trials, the incidence of any ad-
plant users (17.9 min).9 verse effects was 72%. Only 47% of these were judged to
A recent open, multicenter study16 was performed to de- be drug-related.17 Menstrual disturbances include infre-
termine the contraceptive reliability, safety, and acceptabil- quent bleeding, amenorrhea, prolonged bleeding, and fre-
ity of Implanon. The trial involved 21 centers in nine dif- quent bleeding.18 Analysis of bleeding patterns confirmed
ferent countries and lasted three years. The study included that bleeding and spotting averaged 15.9–19.3 days and
635 healthy, sexually active women with childbearing po- 2.2–2.7 episodes per 90-day reference period. The number
tential (age 18– 40 y). Women were included if the men- of bleeding days reported was 7.5–10 days. These effects
strual cycle length was between 24 and 35 days; and were were greater during the first year of use. Dysmenorrhea
excluded if they were pregnant, breast-feeding, or weighed improves or disappears in 82% of affected women. Ane-
above or below 80 –130% of ideal body weight. Medica- mia has not been reported with implant use; in fact, mean
tions with hepatic enzyme–inducing potential were prohib- hemoglobin values increased by 0.64 g/dL by the end of
ited during the study. Insertion of the implant in the inner the third year.18
aspect of the nondominant upper arm occurred between
days 1–5 of menses. Assessments of body height, weight,
blood pressure, and physical and pelvic examinations (in-
cluding Pap smears) were performed at baseline. These pa- Table 2. Incidence of Adverse Effects of Implanon17,18
rameters, as well as bleeding changes, adverse effects, and
Adverse Event Incidence (%)
implant site were monitored approximately every three
months during the study. The physical and pelvic examina- Overall incidence 72
tions, however, were reassessed once every year or at the Drug-related 47
time of implant removal. Forty-one percent of the women Serious adverse eventsa 0.7
were smokers. Menstrual irregularitiesb
infrequent bleeding 26.9
No pregnancies occurred during treatment, resulting in a amenorrhea 18.6
Pearl Index of 0 (95% CI 0.0 to 0.2). The incidence of ear- prolonged bleeding 15.1
ly discontinuation at six, 12, 24, and 36 months was 10%, frequent bleeding 7.4
10%, 11%, and 6%, respectively. Bleeding irregularities Weight gain (>10% more than at baseline)c 20.7
contributed to 17.2% of implant discontinuation after two Acned 15.3
years. Dysmenorrhea improved in 97% of affected wom- Breast pain 9.1
en. Acne, the most frequently reported nonbleeding ad- Headache 8.5
verse effect, improved in 12.8% of patients and worsened Local pain at implant site 2.6
in 12.6% of patients. Clinically significant increase in sys- Increase in BPe
systolic 0.4
tolic and diastolic pressures occurred in 0.8% and 1.1% of diastolic 0.7
patients, respectively. A systolic increase of >20 mm Hg or Cutaneous allergies several cases
a diastolic increase of >10 mm Hg was considered clinical-
a
ly significant. Mean blood pressure readings decreased Reports of serious adverse events that may be drug-related include pa-
pilloma, transient ischemic attacks, chest pain/tachycardia, breast fi-
over time. Approximately 20% of patients experienced an broadenosis, uterine fibroid, ovarian cyst, cervical dysplasia, and tera-
increase in body mass (body mass index increase by toma.
b
>10%). This increase resulted in implant removal in 2.4% The incidence of dysmenorrhea was reduced.
c
The incidence of weight increase reported as drug-related was 6.4%,
of patients. Among the women who weighed >75 kg at the with a gradual mean increase of 1.5–2% per year.
start of the study, 50 serious adverse events were reported. d
Individual studies have shown improvement of acne in many subjects.
e
Only six cases, including uterine fibroid, ovarian cyst, in- Some studies have shown both systolic and diastolic BPs decreased
slightly in some patients.
traductal papilloma, headache, transient ischemic attack,

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The majority of patients experienced a 3.7-kg weight
gain (maximum 22 kg, minimum 1.5 kg) by the end of the
first treatment year.8 The mean body mass index increased
by 3.5%.16 A few cases of weight loss were reported. An inte-
grated analysis17 reported weight gain in 20.7% of patients;
only 6.4% of these were judged to be drug-related. The
gradual increase in weight approached 1.5–2.0% per year.
Lipid profiles remained stable during the course of treat-
ment.12 Changes in serum apolipoproteins AI, AII, and B
did not exceed normal laboratory values.19 The effects on
the hemostatic system were minimal and not indicative of
increased risk for thrombosis. Liver function changes were
characterized by increases in total bilirubin by 11.85% (p <
0.003) and γ-glutamyl transferase by 9.81% (p < 0.019).
Both alanine aminotransferase and aspartate aminotrans-
ferase decreased by 4.42% and 8.17%, respectively.20
The effects of 3-KDSG on acne and blood pressure
were favorable in some patients. Acne improved in 12.8%
of affected women.16 Both systolic and diastolic pressures
decreased slightly.9,16 The integrated analysis did not report
favorable effects on acne and blood pressure. The develop-
ment or worsening of acne was observed in 15.3% of wom-
en and an increase in blood pressure in 0.4–0.7% of wom-
en. Some patients (9.1%) experienced breast pain.17
One study21 showed that endometrial thickness was re-
duced (mean <4 mm) and endometrial histology was either
inactive or weakly proliferative in users of Implanon at the
end of two years. Cervical cytology remained unchanged.
This two-year study concluded that there was no evidence
of increased risk of endometrial hyperplasia, endometrial
carcinoma, cervical intraepithelial neoplasia, or cervical
carcinoma among implant users.
Temporary infertility was observed in all women since
return to ovulation did not occur until three to six weeks
after implant removal.8-10 Normal pregnancies were ob-
served within three months of discontinuation.22 Ninety-
one percent of subjects resumed normal menses within
three months of implant removal.16 Other adverse effects
reported include headache (8.5%) and short-lived, mild
pain at implant site after insertion and removal (2.6%).17
Although infrequent, cutaneous allergies occurred in sever-
al cases.12
Early discontinuation of the implant resulted primarily
from bleeding irregularities (Table 3); including frequent
irregular bleeding, prolonged menstrual flow, spotting, and
heavy menstrual flow. Frequent irregular bleeding account-
ed for approximately 50% of bleeding-related discontinua-
tions. Amenorrhea (0.5%) was rarely responsible for dis-
continuation (0.9%).18 Other causes for withdrawals in-
clude weight increase (1.5%), acne (1%), decreased libido
(0.7%), depression (0.4%), and headache (0.3%).17
Contraindications
Desogestrel implants are contraindicated in patients
with known or suspected pregnancy. Women who are hy-
persensitive to the drug should not use the implant. Pa-
tients with unexplained abnormal vaginal bleeding, severe
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Implanon: A Critical Review
hepatic disease (including liver tumors), or carcinoma of
the breast should avoid hormonal contraceptives, including
implants.
Warnings
Changes in menstrual bleeding patterns usually occur
with the use of the implant, most notably during the first
year of use.12 Most women may experience irregularities
ranging from spotting between cycles or prolonged bleeding/
spotting episodes to amenorrhea.8,9,12,22 These symptoms
may obscure detection of endometrial or cervical cancer.
Women who experience six or more weeks of amenorrhea
after normal menstruation should be tested for pregnancy.
The implant should be immediately removed once preg-
nancy is confirmed or detected. Persistent follicular cysts
with a diameter of >30 mm have also been observed.23 The
development of enlarged follicles may correlate with ab-
normal menstrual blood loss and high serum concentra-
tions of 3-KDSG.12 These cysts are asymptomatic and re-
solve spontaneously within seven to 90 days.9,12 No cases
of cystic rupture or need for surgical puncture have been
reported. One case of ectopic pregnancy occurred in an
early clinical trial using subtherapeutic dosages of deso-
gestrel.12 Although rare, ectopic pregnancy should be ruled
out in patients with lower abdominal pain or in those who
become pregnant during treatment. This is especially im-
portant in women with serum 3-KDSG concentrations
≤280 pg/mL.12,23 In one case, benign fibroadenoma of the
breast was diagnosed on surgical removal of the tumor.12
Despite this case, a correlation between the use of combi-
nation oral contraceptives and an increased risk of breast
cancer has not been established.23 The risk of breast cancer
among users of contraceptive implants needs to be studied
further.
Safety in Pregnancy and Lactation
Although not yet classified by the Food and Drug Ad-
ministration, desogestrel and other progestins are contra-
Table 3. Incidence of Adverse Effects Related to
Early Discontinuation of Implanon17,18
Adverse Event Incidence (%)
Vaginal bleeding irregularities 9.6
frequent bleeding 5.6
prolonged menstrual flow 1.9
spotting 1.8
heavy menstrual flow 0.3
Amenorrhea 0.9
Adverse events other than changes in bleeding 7.3
patterns
increased weight 1.5
acne 1.0
decreased libido 0.7
depression 0.4
headache 0.3
others (rare) 3.4
The Annals of Pharmacotherapy ■ 2001 March, Volume 35 ■ 333
J Le and C Tsourounis
indicated in pregnancy or suspected pregnancy. Addition-
ally, progestins should not be used if there is a history of
ectopic pregnancy, during the first four months of pregnan-
cy, or in diagnostic tests for pregnancy. No information is
currently available to confirm desogestrel safety in lacta-
tion. The American Academy of Pediatrics Committee on
Drugs24 considers progestin-only contraceptives compati-
ble with breast feeding.
Drug Interactions
Drug interactions with desogestrel implants have not
been systematically studied. However, medications that in-
crease the metabolism of progestins via hepatic enzyme in-
duction may also decrease the serum concentrations of
3-KDSG.5 Phenytoin, carbamazepine, rifampin, and griseo-
fulvin are known inducers of hepatic enzymes and therefore
may decrease 3-KDSG below the concentration required to
prevent conception.
Dosage and Administration
Implanon provides effective contraception by releasing
the progestational agent 3-KDSG.5 The implant system is a
single rod that contains a core of 68 mg of 3-KDSG with a
membrane of ethylene vinyl acetate.10,14,15,20,25 This nonbio-
degradable rod is 2 mm in diameter and 40 mm long.9,22
Effective contraception lasts for three years with a maxi-
mum of four years.16,26 Insertion and removal should be
performed only by trained medical professionals. Under
aseptic conditions, the implants are inserted in the non-
dominant arm approximately 6–8 cm above the elbow.8,25
Insertion should occur between days 1 and 5 of menses to
prevent the need for a second method of contraception.9
Clinical efficacy has been demonstrated when insertion oc-
curs within the first week of the menstrual cycle.11,12 The
site should be meticulously cleansed and anesthetized prior
to insertion of the preloaded sterile applicator. The needle
is introduced at a small angle under the skin and the obtu-
rator is turned 90˚. While keeping the obturator fixed in
position, the cannula is slowly removed from the arm.25 A
pressure dressing is applied and removed after 48 hours.8
The implant is invisible yet palpable. The average insertion
time ranges between 1.1 and 2.2 minutes.16,25 The implant
should be dislodged within three years of use, although ef-
ficacy may be retained for an additional year.9,22,26 Mean re-
moval time is reported as 2.6 –5.4 minutes.16,25 The “pop
out” method is used to remove the implant. This minor
surgery involves making a vertical 2-mm incision at the
distal tip of the implant and pushing the rod until it pops
out.25 A few complications have been observed with the in-
sertion and removal of the implant: one case of bleeding,
one case in which the rod came out of the skin, and one
case in which the tip of the implant was visible. Complica-
tions during removal were usually caused by deep inser-
tion or significant fibrosis at the implant site.16,25 Pain
(1.9%), swelling (0.5%), redness (0.3%), and hematoma
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(0.2%) at the implant site were minor problems reported
during the study.25 Dosage adjustment in emaciated or
obese patients was not assessed in current clinical trials.
Women weighing <50 kg appear to have higher serum
concentrations of 3-KDSG.14,15
Patient Education
Patients should be instructed that desogestrel implants
provide contraception for at least three years, with a maxi-
mum of four years. Implants do not protect against sexual-
ly transmitted diseases. However, pelvic inflammatory dis-
ease is less likely to develop when progestin-only contra-
ceptives are used. The thickening of cervical mucus hinders
the migration of bacteria into the uterus and fallopian tubes
that may cause pelvic inflammatory disease.27 Patients
should also be properly informed on the common adverse
effects associated with implant use to prevent premature
discontinuation. Common adverse effects include irregular
bleeding and weight gain. Most women will develop irreg-
ular bleeding patterns ranging from increased bleeding/
spotting to amenorrhea, especially within the first year of
use. A second common experience is weight gain, which
can be easily controlled by adequate nutrition and exercise.
Acne, breast pain, or headache may occur in some cases.
Although recent studies have not confirmed increased risk
of thromboembolic, cardiovascular, or hepatic disease in
users of hormonal implants, patients should be advised to
report any related symptoms. Additionally, annual Pap
smears and breast examinations are highly recommended
since use of steroidal contraceptives may increase the inci-
dence of cervical and breast tumors.
Summary
Desogestrel implants appear to be an effective contra-
ceptive method providing protection for at least three years
(Table 4). Implants do not require stringent compliance as
oral contraceptive agents do. Since desogestrel is a potent
progestin, inhibition of ovulation occurs within one day of
implantation. Insertion and removal of this single rod is
easier than with the six subdermal capsules of Norplant,
and only minor complications have been documented in
rare cases. After implant removal, fertility returns within
one month. Adverse effects are mild and primarily consist
of abnormal bleeding, weight gain, acne, breast pain, and
headache. Implanon displays excellent efficacy and ap-
pears to be a good addition to the currently available con-
traceptives.
Jennifer Le PharmD, School of Pharmacy, University of California
at San Francisco
Candy Tsourounis PharmD, Assistant Clinical Professor, Acting
Director, Drug Information Analysis Service, Department of Clinical
Pharmacy, School of Pharmacy, University of California at San Fran-
cisco, San Francisco, CA
Reprints: Candy Tsourounis PharmD, Department of Clinical Phar-
macy, School of Pharmacy, University of California at San Francis-
co, 521 Parnassus, C-152, San Francisco, CA 94143-0622, FAX
415/502-0792, E-mail candy@itsa.ucsf.edu
www.theannals.com

Table 4. Summary of Implanon
Name desogestrel implants
Brand/manufacturer Implanon, by Organon International
BV
Therapeutic category contraceptive, progestin implant
Use prevention of pregnancy for 3 y
Mechanism of action active metabolite 3-KDSG inhibits
ovulation by altering the hypo-
thalamic–pituitary–ovarian mecha-
nism that downregulates luteinizing
hormone; interferes with implantation
by inhibiting endometrial prolifera-
tion; hinders sperm migration by in-
creasing viscosity of cervical mucus
Pharmacokinetics
absorption and distribution system releases 3-KDSG at 60 µg/d
during first 4 wk, followed by 40, 35,
and 25–30 µg/d at the end of the
first, second, and third years,
respectively; the average serum con-
centration reached within the first
year is 176–196 pg/mL and declines
to 156 pg/mL at the end of the third
year
metabolism unknown
protein binding primarily to albumin
elimination unknown route; half-life of 25 h; clear-
ance of 7.5 L/h with no accumulation
return of ovulation 3–6 wk on implant removal
return of normal menses 3 mo on implant removal
Warnings women with ≥6 wk amenorrhea
should be tested for pregnancy;
ectopic pregnancy must be ruled out
in these patients and also in patients
who experience lower abdominal
pain; menstrual irregularities may
obscure detection of endometrial or
cervical cancer; follicular cysts may
develop and are indistinguishable
from ovarian cysts; unknown poten-
tial risk of breast cancer
Contraindications known or suspected pregnancy; hy-
persensitivity to any components of
the implant; unexplained abnormal
vaginal bleeding
Drug interactions may decrease contraceptive activity
when given with hepatic enzyme
inducers including phenytoin, carba-
mazepine, rifampin, and griseofulvin
Dosage and administration Implanon is a single rod (2 mm in
diameter and 40 mm long) that con-
tains 60 mg of 3-KDSG with a mem-
brane of ethylene vinyl acetate;
these implants are inserted between
days 1 and 5 of menses in the upper,
inner aspect of the nondominant arm
3-KDSG = 3-keto-desogestrel.
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EXTRACTO
OBJETIVO: Evaluar la información clínica de Implanon como un método
anticonceptivo de uso prolongado y en específico repasar la eficacia y el
perfil de efectos adversos.
FUENTES DE INFORMACIÓN: Búsqueda en MEDLINE de la literatura
primaria y artículos de repaso publicados hasta el 1999. La búsqueda se
The Annals of Pharmacotherapy ■ 2001 March, Volume 35 ■ 335
J Le and C Tsourounis
limitó a estudios en humanos. Algunas referencias se identificaron por
fuentes secundarias.
SELECCIÓN DE DATOS: Se repasaron estudios farmacocinéticos y
farmacodinámicos y estudios clínicos que incluían la eficacia y
seguridad de los implantes de desogestrel.
SÍNTESIS: Implanon es el más reciente de los anticonceptivos de
implantación que ha completado los estudios clínicos de fase III
mundialmente. Consiste de un tubo con un centro de desogestrel y una
membrana de acetato de etileno vinílico. La inhibición de la ovulación
ocurre a partir de un día de la implantación y dura hasta tres años. La
fertilidad regresa un mes después de la remoción del implante. Se ha
documentado que la inserción y remoción por un médico capacitado es
sencilla y con complicaciones menores. Los efectos adversos son leves y
consisten primordialmente de sangrado anormal, ganancia de peso, acné,
dolor en las mamas, y dolor de cabeza.
CONCLUSIONES: Los datos sobre Implanon indican que es efectivo
previniendo la concepción por períodos prolongados con efectos
adversos limitados. Este es una alternativa que se añade a los
anticonceptivos disponibles en la actualidad.
Sonia I Lugo
RÉSUMÉ
OBJECTIF: Évaluer les informations cliniques portant sur Implanon en
tant que contraceptif à long terme et évaluer spécifiquement son
efficacité et son profil d’effets indésirables.
336 ■ The Annals of Pharmacotherapy ■ 2001 March, Volume 35
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SOURCE DE DONNÉES: Une recherche sur MEDLINE a permis de retracer
les articles originaux et de revue publiés jusqu’en 1999. La recherche a
été limitée aux humains et des références secondaires ont été identifiées
à l’aide d’autres sources.
SÉLECTION DES ÉTUDES ET EXTRACTION DES DONNÉES: Les articles
sélectionnés incluent les études pharmacocinétiques, pharmaco-
dynamiques, d’efficacité, et d’innocuité. Les études ont été évaluées
selon leur pertinence.
RÉSUMÉ: Implanon est l’implant contraceptif le plus récent à avoir
complété des études mondiales de phase 3. Il consiste en un cylindre
unique contenant 68 mg de 3-céto-désogestrel avec une membrane
d’éthylène vinyle acétate. L’ovulation est inhibée un jour post-
implantation, et l’effet contraceptif dure trois ans. Le retour à la fertilité
se fait un mois après le retrait de l’ implant. La pose et le retrait par un
professionnel entraîné sont simples et seulement des complications
mineures ont été documentées. Les effets indésirables consistent surtout
en saignements anormaux, gain de poids, acné, mastalgie, et maux de
tête.
CONCLUSIONS: Les données sur Implanon indiquent qu’il apporte une
contraception efficace à long terme avec des effets indésirables limités.
Cela semble être un bon ajout aux contraceptifs actuellement
disponibles.
Jean Longtin
www.theannals.com