Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1244
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Implanon (Implant)
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All healthcare
providers performing insertions and/or removals of IMPLANON���must
receive instruction and training and where appropriate, supervision
prior to inserting or removing IMPLANON���. Insert IMPLANON���subdermally
in the inner side of the upper arm (non-dominant arm) about 6-8 cm (2��-3
inches) above the elbow crease overlying the groove between the biceps
and the triceps. See INSTRUCTIONS FOR
INSERTION AND REMOVAL. IMPLANON���must be inserted by the
expiration date stated on the packaging. Remove IMPLANON���no later than three years after the date of
insertion.<br/>When to Insert
IMPLANON���: IMPORTANT: Rule out pregnancy before
inserting IMPLANON���. Timing of insertion depends on the
patient's recent history, as follows:<br/>1. No preceding hormonal
contraceptive use in the past month: Counting the first day of menstruation as���Day 1���,
IMPLANON���must be inserted between Days 1 through 5,
even if the woman is still bleeding.<br/>2. Switching from a combination
hormonal contraceptive: IMPLANON���may be inserted:<br/>3. Switching from a progestin-only
method: There are several types of progestin-only methods.
IMPLANON���insertion must be performed as follows:<br/>4. Following first-trimester abortion
or miscarriage:<br/>5. Following delivery or a
second-trimester abortion: If inserted as recommended
above, back-up contraception is not necessary. If
deviating from the recommended timing of insertion,
rule out pregnancy and use back-up non-hormonal
contraception for 7 days after IMPLANON���insertion.
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IMPLANON���(etonogestrel implant) is an off-white, non-biodegradable,
etonogestrel-containing single sterile rod implant for subdermal use.
The implant is 4 cm in length with a diameter of 2 mm (see Figure 1).
Each IMPLANON���rod consists of an ethylene vinylacetate (EVA) copolymer
core, containing 68 mg of the synthetic progestin etonogestrel (ENG),
surrounded by an EVA copolymer skin. The release rate is 60-70��g/day in
week 5-6 and decreases to approximately 35-45��g/day at the end of the
first year, to approximately 30-40��g/day at the end of the second year,
and then to approximately 25-30��g/day at the end of the third year.
IMPLANON���is a progestin-only contraceptive and does not contain
estrogen. IMPLANON���does not contain latex and is not radio-opaque. ENG
[13-Ethyl-17-hydroxy-11-methylene-18,19-dinor-17��-pregn-4-en-20-yn-3-one],
structurally derived from 19-nortestosterone, is the synthetic
biologically active metabolite of the synthetic progestin desogestrel.
It has a molecular weight of 324.46 and the following structural
formula:
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Pharmacodynamics: The
contraceptive effect of IMPLANON���is achieved by several
mechanisms that include suppression of ovulation, increased
viscosity of the cervical mucus, and alterations in the
endometrium.<br/>Pharmacokinetics:<br/>Absorption: After subdermal insertion of IMPLANON���, ENG is released
into the circulation and is approximately 100%
bioavailable. The
mean peak serum concentrations in 3 pharmacokinetic
studies ranged between 781 and 894 pg/mL and were
reached within the first few weeks after insertion. The
mean serum ENG concentration decreases gradually over
time declining to 192 - 261 pg/mL at 12 months (n=41),
154���194 pg/mL at 24 months (n=35), and 156���177 pg/mL
at 36 months (n=17). The pharmacokinetic profile of
IMPLANON���from one of 3 pharmacokinetic studies is shown
in Figure 2.<br/>Distribution: The
apparent volume of distribution averages about 201 L.
ENG is approximately 32% bound to sex hormone binding
globulin (SHBG) and 66% bound to albumin in
blood.<br/>Metabolism: In vitro
data shows that ENG is metabolized in liver microsomes
by the cytochrome P450 3A4 isoenzyme. The biological
activity of ENG metabolites is unknown.<br/>Excretion: The
elimination half-life of ENG is approximately 25 hours.
Excretion of ENG and its metabolites, either as free
steroid or as conjugates, is mainly in urine and to a
lesser extent in feces. After removal of IMPLANON���, ENG
concentrations decreased below sensitivity of the assay
by one week.<br/>Special Populations:<br/>Overweight Women: The
effectiveness of IMPLANON���in overweight women has not
been defined because women who weighed more than 130% of
their ideal body weight were not studied. However, serum
concentrations of ENG are inversely related to body
weight and decrease with time after insertion. It is
therefore possible that with time IMPLANON���may be less
effective in overweight women, especially in the
presence of other factors that decrease etonogestrel
concentrations such as concomitant use of hepatic enzyme
inducers.<br/>Race: No
formal studies were conducted to evaluate the effect of
race on the pharmacokinetics of IMPLANON���.<br/>Hepatic
Insufficiency: No
formal studies were conducted to evaluate the effect of
hepatic disease on the pharmacokinetics of IMPLANON���.
However, ENG is metabolized by the liver, and therefore
use in patients with active liver disease is
contraindicated.<br/>Renal Insufficiency: No
formal studies were conducted to evaluate the effect of
renal disease on the pharmacokinetics of
IMPLANON���.
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IMPLANON���(etonogestrel implant) should not be used in women who have
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One IMPLANON���(etonogestrel implant) package consists of a single
rod implant containing 68 mg etonogestrel that is 4 cm in length and 2
mm in diameter. IMPLANON���is pre-loaded in the needle of a disposable
applicator. The applicator consists of acrylonitrile-butadiene-styrene
body with a stainless steel needle and a polypropylene shield. The
sterile applicator containing IMPLANON���is packed in a blister pack. NDC
0052-0272-01<br/>Storage: Store
IMPLANON���(etonogestrel implant) at 25��C (77��F); excursions
permitted to 15-30��C (59-86��F) [see USP Controlled Room
Temperature]. Protect from light. Avoid storing IMPLANON���in
direct sunlight or at temperatures above 30��C (86��F). Rx only
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1. General: Women should be informed that this
product does not protect against infection from HIV (the
virus that causes AIDS) or other sexually transmitted
diseases. IMPORTANT: Pregnancy must be excluded
before inserting IMPLANON���.<br/>2. Physical
Examination and Follow-up: A complete medical evaluation, including history and
physical examination and relevant laboratory tests, should be
performed prior to IMPLANON���insertion or reinsertion. It is
good medical practice for patients using IMPLANON���to have
regular physical examinations. In case of undiagnosed,
persistent, or recurrent abnormal vaginal bleeding, appropriate
measures should be conducted to rule out malignancy. Women with
a family history of breast cancer or who have breast nodules
should be monitored with particular care.<br/>3. Information for
the Patient: Provide
your patient with a copy of the Patient Labeling and ensure that
she understands the information in the Patient Labeling before
insertion and removal. A USER CARD and consent form are included
in the packaging, Have the patient complete a consent form and
retain it in your records. The USER CARD should be filled out
and given to the patient after IMPLANON���insertion so that she
will have a record of the location of IMPLANON���and when
IMPLANON���should be removed.<br/>4. Weight Gain: In clinical
studies, mean weight gain in U.S. IMPLANON���users was 2.8 pounds
after one year and 3.7 pounds after two years. How much of the
weight gain was related to IMPLANON���is unknown. In studies,
2.3% of IMPLANON���users reported weight gain as the reason for
having IMPLANON���removed.<br/>5. Carbohydrate and
Lipid Metabolic Effects: IMPLANON���may induce mild insulin resistance and small changes in glucose
concentrations of unknown clinical significance. Women with
diabetes or impaired glucose tolerance should be carefully
observed while using IMPLANON���. Women who
are being treated for hyperlipidemias should be followed closely
if they elect to use hormonal contraceptives. Some progestins
may elevate LDL levels and may render the control of
hyperlipidemias more difficult.<br/>6. Liver Function: If jaundice
develops in any patient using IMPLANON���, remove IMPLANON���. The
hormone in IMPLANON���may be poorly metabolized in patients with
impaired liver function.<br/>7. Depression: Women with
a history of depression should be carefully observed.
Consideration should be given to removing IMPLANON���in patients
who become significantly depressed.<br/>8. Contact Lenses: Contact
lens wearers who develop visual changes or changes in lens
tolerance should be assessed by an ophthalmologist.<br/>9. Drug
Interactions:<br/>Changes in Contraceptive
Effectiveness Associated with Co-Administration of Other
Drugs:<br/>Increase in Plasma Hormone
Levels Associated with Co-Administered Drugs: Inhibitors of hepatic enzymes such as itraconazole or
ketoconazole may increase plasma hormone
levels.<br/>10. Interactions
with Laboratory Tests: Certain
endocrine tests may be affected by IMPLANON���use:<br/>11. Carcinogenesis
and Mutagenesis and Impairment of Fertility: In a
24-month carcinogenicity study in rats with subdermal implants
releasing 10 and 20��g etonogestrel (ENG) per day (equal to
approximately 1.8-3.6 times the systemic steady state exposure
of women using IMPLANON���), no drug-related carcinogenic
potential was observed. ENG was not genotoxic in the in vitro Ames/Salmonella
reverse mutation assay, the chromosomal aberration assay in
Chinese hamster ovary cells or in the in vivo mouse micronucleus
test. Fertility returned after withdrawal from
treatment.<br/>12. Pregnancy: IMPLANON���is not indicated for use during pregnancy . Teratology studies have been performed in rats and
rabbits, respectively using oral administration up to 390 and
790 times the human IMPLANON���dose (based upon body surface) and
revealed no evidence of fetal harm due to ENG exposure. Studies have revealed no increased risk of birth defects
in women who have used combination oral contraceptives before
pregnancy or during early pregnancy. There is no evidence that
the risk associated with IMPLANON���is different from that of
combination oral contraceptives. IMPLANON���should be removed if maintaining a
pregnancy.<br/>13. Nursing Mothers: Based on
limited data, IMPLANON���may be used during lactation after the
4th postpartum week. Use of IMPLANON���before the 4th postpartum
week has not been studied. Small
amounts of ENG are excreted in breast milk. During the first
months after IMPLANON���insertion, when maternal blood levels of
ENG are highest, about 100 ng of ENG may be ingested by the
child per day based on an average daily milk ingestion of 658
mL. Based on daily milk ingestion of 150 mL/kg, the mean daily
infant ENG dose one month after insertion of IMPLANON���is about
2.2% of the weight-adjusted maternal daily dose, or about 0.2%
of the estimated absolute maternal daily dose. The health of
breast-fed infants whose mothers began using IMPLANON���during
the 4th to 8th week postpartum (n=38) was evaluated in a
comparative study with infants of mothers using a non-hormonal
IUD (n=33). They were breast-fed for a mean duration of 14
months and followed up to 36 months of age. No significant
effects and no differences between the groups were observed on
the physical and psychomotor development of these infants. No
differences between groups in the production or quality of
breast milk were detected. Healthcare
providers should discuss both hormonal and non-hormonal
contraceptive options, since steroids may not be the initial
choice for these patients.<br/>14. Return to
Ovulation: In clinical trials, pregnancies occurred as early as
during the first week after removal of IMPLANON���. Therefore, a
patient should re-start contraception immediately after removal
of IMPLANON���if she still needs to prevent
pregnancy.<br/>15. Fluid Retention: Steroid
contraceptives may cause some degree of fluid retention. They
should be prescribed with caution, and only with careful
monitoring, in patients with conditions which might be
aggravated by fluid retention. It is unknown if IMPLANON���causes
fluid retention.<br/>16. Pediatric Use: Safety and
efficacy of IMPLANON���have been established in women of
reproductive age. Safety and efficacy are expected to be the
same for postpubertal adolescents. However, no clinical studies
have been conducted in women less than 18 years of age. Use of
this product before menarche is not indicated.<br/>17. Geriatric Use: This
product has not been studied in women over 65 years of age and
is not indicated in this population.
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Insertion of
multiple rods has been reported. Overdosage may result if more than one
IMPLANON���(etonogestrel implant) rod is in place. In case of suspected
overdose, IMPLANON���should be removed. It is important to remove the
IMPLANON���rod or other contraceptive implant(s) before inserting a new
IMPLANON���rod.
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etonogestrel
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Implanon (Implant)
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See WARNINGS and PRECAUTIONS for additional important adverse events. In clinical trials including 942 subjects, bleeding
irregularities were the most common adverse event causing
discontinuation of IMPLANON���. (see following Table) Adverse events that were reported by more than 5% of subjects in
clinical trials appear in the following Table. Other���Less Common Adverse
Events���Reported in Less Than 5% of Subjects in Clinical
Trials Include: Allergic Reaction, Alopecia, Anorexia, Anxiety, Appetite
Increased, Arthralgia, Asthenia, Asthma, Breast Discharge, Breast
Enlargement, Breast Fibroadenosis, Cervical Smear Test Positive,
Constipation, Coughing, Crying Abnormal, Diarrhea, Dyspepsia, Dysuria,
Edema, Edema Generalized, Fatigue, Fever, Flatulence, Gastritis, Hot
Flushes, Hypertension, Hypoasthesia, Injection Site Reaction, Insomnia,
Lactation Nonpuerperal, Libido Decreased, Migraine, Myalgia, Otitis
Media, Ovarian Cyst, Pelvic Cramping, Premenstrual Tension, Pruritus,
Pruritus Genital, Rash, Rhinitis, Sexual Function Abnormal, Skeletal
Pain, Somnolence, Vaginal Discomfort, Vein Varicose, Vision Abnormal,
Vomiting, and Weight Decrease. Hypertrichosis has also been reported with use of progestin-only
contraceptives. Implant site
complications were reported by 3.6% of subjects during any of the
assessments in clinical trials. Pain was the most frequent implant site
complication, reported during and/or after insertion, occurring in 2.9%
of subjects. Additionally, hematoma, redness, and swelling were reported
by 0.1%, 0.3%, and 0.3% of patients, respectively. See also WARNINGS,
COMPLICATONS OF INSERTION AND REMOVAL.
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A. WARNINGS BASED
ON EXPERIENCE WITH IMPLANON���AND OTHER PROGESTIN-ONLY CONTRACEPTIVES:<br/>1. Complications of Insertion and
Removal: IMPLANON���should be inserted
subdermally so that it is palpable after insertion.
Failure to insert IMPLANON���properly may go
unnoticed unless the implant is palpated immediately
after insertion. Deep insertions may lead to
difficult or impossible removals. Failure to remove
IMPLANON���may result in infertility, ectopic
pregnancy, or inability to stop a drug-related
adverse event. Undetected failure to insert
IMPLANON���may lead to an unintended pregnancy. See
INSTRUCTIONS FOR INSERTION AND
REMOVAL. In clinical trials, 1.0% of patients had
complications at implant insertion and 1.7% had
complications at implant removal. Complications expected
of a minor surgical procedure, such as pain,
paresthesias, bleeding, hematoma, scarring or infection,
have been reported. Occasionally in post-marketing use,
implant insertions have failed because the implant fell
out of the needle or remained in the needle during
insertion. Implant removals may be difficult because the
implant is deep, not palpable, encased in fibrous
tissue, or has migrated. Implants have broken during
difficult removals. Deep insertions may result in the need for a
surgical procedure in an operating room in order to
remove IMPLANON���. Any of the possible complications of
surgery may occur. In post-marketing use there have been
cases of failure to localize and remove the implant,
probably due to deep insertion. There has been one case
of an intravascular insertion reported post-marketing
which led to inability to remove the implant. If infection develops at the insertion site,
start suitable treatment. If infection persists, remove
IMPLANON���. Incomplete insertions or infections may lead
to expulsion.<br/>2. Ectopic Pregnancies: Be alert to the possibility of an ectopic
pregnancy among patients using IMPLANON���who become
pregnant or complain of lower abdominal pain. Although
ectopic pregnancies should be uncommon among patients
using IMPLANON���, a pregnancy that occurs in a patient
using IMPLANON���may be more likely to be ectopic than a
pregnancy occurring in a patient using no
contraception.<br/>3. Bleeding
Irregularities: Patients who use IMPLANON���are likely to have changes
in their vaginal bleeding patterns, which are often
unpredictable. These may include changes in bleeding
frequency or duration, or amenorrhea. Patients should be
counseled regarding unpredictable bleeding
irregularities so that they know what to expect.
Abnormal bleeding should be evaluated as needed to
exclude pathologic conditions or pregnancy. In
clinical trials, bleeding changes were the single most
common reason for stopping treatment with IMPLANON���(11.1%, or 105 of 942 patients using IMPLANON���). Most
patients stopped treatment with IMPLANON���because of
irregular bleeding (10.8%), but some stopped because of
amenorrhea (0.3%). In these studies, patients using
IMPLANON���had an average of 17.7 days of bleeding or
spotting every 90 days (based on 3315 intervals of 90
days recorded by 780 patients). The percentages of
patients having 0, 1-7, 8-21, or>21 days of spotting
or bleeding over a 90-day interval while using IMPLANON���is shown in the following table. Bleeding patterns observed with use of IMPLANON���for up to 2 years, and the proportion of 90-day
intervals with these bleeding patterns, are summarized
in the following table.<br/>4. Interaction with Anti-Epileptic
and Other Drugs: IMPLANON���is not recommended for women who
chronically take drugs that are potent hepatic enzyme
inducers because etonogestrel levels may be
substantially reduced in these women. See also PRECAUTIONS, Drug
Interactions.<br/>5. Ovarian Cysts: If
follicular development occurs, atresia of the follicle
is sometimes delayed, and the follicle may continue to
grow beyond the size it would attain in a normal cycle.
Generally, these enlarged follicles disappear
spontaneously. Rarely, they can require
surgery.<br/>6. Thrombosis: There have been post-marketing reports of serious
thromboembolic events, including cases of pulmonary
emboli (some fatal) and strokes, in patients using
IMPLANON���. IMPLANON���should be removed in the event of a
thrombosis. Consider removal of IMPLANON���in case of
long-term immobilization due to surgery or illness.
Women with a history of thromboembolic disorders should
be made aware of the possibility of a recurrence. See
also WARNINGS BASED ON EXPERIENCE WITH COMBINATION
(PROGESTIN PLUS ESTROGEN) ORAL
CONTRACEPTIVES.<br/>B. WARNINGS BASED
ON EXPERIENCE WITH COMBINATION (PROGESTIN PLUS ESTROGEN) ORAL
CONTRACEPTIVES:<br/>1. Thromboembolic Disorders and
Other Vascular Problems: Thromboembolism: Epidemiological investigations have
associated the use of combination hormonal
contraceptives with an increased incidence of venous
thromboembolism (VTE, deep venous thrombosis, retinal
vein thrombosis, and pulmonary embolism). The
use of combination hormonal contraceptives is associated
with increased risks of several serious conditions
including myocardial infarction, thromboembolism, and
stroke, although the risk of serious morbidity or
mortality is very small in healthy women without
underlying risk factors. The risk increases
significantly in thepresence of other underlying risk
factors such as hypertension, hyperlipidemias, obesity,
and diabetes.<br/>2. Cigarette Smoking: Cigarette smoking increases the risk of serious
cardiovascular side effects from the use of combination
hormonal contraceptives. This risk increases with age
and with heavy smoking (15 or more cigarettes per day)
and is quite marked in women over 35 years old who
smoke. While this is believed to be an estrogen-related
effect, it is not known whether a similar risk exists
with progestin only methods. However, patients should be
strongly advised not to smoke.<br/>3. Elevated Blood
Pressure: An
increase in blood pressure has been reported in women
taking combination hormonal contraceptives and this
increase is more likely with continued use and with
those users who are older. Studies have shown that the
incidence of hypertension increases with increasing
concentrations of progestins. Women with a history of hypertension-related diseases
or renal disease should be discouraged from using
hormonal contraceptives. If women with hypertension
elect to use hormonal contraceptives, they should be
monitored closely. lf sustained hypertension develops
during the use of hormonal contraceptives, or if a
significant increase in blood pressure does not respond
adequately to antihypertensive therapy, hormonal
contraceptives should be discontinued. For
most women, elevated blood pressure will return to
normal after stopping hormonal contraceptives, and there
is no difference in the occurrence of hypertension
between ever- and never-users.<br/>4. Carcinoma of the Breast and
Reproductive Organs: Women with breast cancer should not use hormonal
contraceptives because breast cancer may be hormonally
sensitive. The
risk of having breast cancer diagnosed may be slightly
increased among current and recent users of combination
oral contraceptives. However, after combination oral
contraceptive discontinuation this excess risk appears
to decrease over time and within 10 years after
cessation the increased risk disappears. Some studies
report an increased risk with duration of use while
other studies do not, and no consistent relationships
have been found with dose or type of steroid. Some
studies have found a small increase in risk for women
who first used combination oral contraceptives before
age 20. Most studies show a similar pattern of risk with
combination oral contraceptive use regardless of a
woman's reproductive history or her family breast cancer
history. In
addition, breast cancers diagnosed in current or ever
combination oral contraceptive users may be less
clinically advanced than in never-users. Some studies suggest that oral contraceptive use has
been associated with an increase in the risk of cervical
intraepithelial neoplasia in some populations of women.
However, there continues to be controversy about the
extent to which such findings may be due to differences
in sexual behavior and other factors. In
spite of many studies on the relationship between
combination oral contraceptive use and breast and
cervical cancers, a cause-and-effect relationship has
not been established.<br/>5. Hepatic Neoplasia: Benign hepatic adenomas have been associated with the
use of combination oral contraceptives, although the
incidence of benign tumors is rare in the United States.
Indirect calculations have estimated the attributable
risk to be in the range of 3.3 cases/100,000 for users,
a risk that increases after four or more years of use.
Rupture of benign hepatic adenomas may cause death
through intra-abdominal hemorrhage. Studies from Britain have shown an increased risk of
developing hepatocellular carcinoma in long-term (>8
years) oral contraceptive users. However, these cancers
are extremely rare in the U.S. and the attributable risk
(the excess incidence) of liver cancers in oral
contraceptive users approaches less than one per million
users.<br/>6. Gallbladder Disease: Earlier studies have reported an increased lifetime
relative risk of gallbladder surgery in users of
combination oral contraceptives and estrogens. More
recent studies, however, have shown that the relative
risk of developing gallbladder disease among combination
oral contraceptive users may be minimal. The recent
findings of minimal risk may be related to the use of
combination oral contraceptive formulations containing
lower doses of estrogens and progestins.
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IMPLANON���(etonogestrel implant) is indicated for women for the prevention of
pregnancy. IMPLANON���is a long-acting (up to 3 years), reversible,
contraceptive method. IMPLANON���must be removed by the end of the third
year and may be replaced by a new IMPLANON���at the time of removal, if
continued contraceptive protection is desired. In clinical trials
involving 923 subjects and 1,854 women-years of IMPLANON���use, the total
exposure in 28-day cycles by year was The clinical trials excluded women who Among women aged 18-35 years of age at entry, six pregnancies
during 20,648 cycles of use were reported. Two pregnancies occurred in
each of Years 1, 2 and 3. Each conception was likely to have occurred
shortly before or within two weeks after IMPLANON���removal. With these
six pregnancies, the cumulative Pearl Index was 0.38 pregnancies per 100
women-years of use. The efficacy of IMPLANON���does not depend on patient
self-administration. IMPLANON���may be less effective in women who are
overweight or who are taking medications that induce liver enzymes. See
CLINICAL
PHARMACOLOGY, Special Populations, Overweight Women, and
PRECAUTIONS, Drug Interactions. The following Table
shows pregnancy rates in the first year of use for other contraceptive
methods.
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Implanon
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