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.
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:
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���.
IMPLANON���(etonogestrel implant) should not be used in women who have
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
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.
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.
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.
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.
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.