A. WARNINGS BASED ON EXPERIENCE WITH IMPLANON™ AND OTHER PROGESTIN-ONLY CONTRACEPTIVES
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 . When IMPLANON™ is inserted too deeply (intramuscular or in the fascia) this may cause neural or vascular damage. Too deep insertions have been associated with paraesthesia (due to neural damage) and migration of the implant (due to intramuscular or fascial insertion), and in rare cases with intravascular insertion. 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.
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.
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.
Percentages of Patients with 0, 1–7, 8–21, or >21 Days of Spotting or Bleeding over a 90-Day Interval while using IMPLANON™
|Total Days of Spotting or Bleeding||Percentage of Patients|
|8 to 21 days||30%||30%||37%|
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.
Bleeding Patterns Using IMPLANON™ during the First 2 Years of Use
|% = Percentage of 90-day intervals with this pattern|
Based on 3,315 recording periods of 90 days duration in 780 women, excluding the first 90 days after implant insertion
|Infrequent||Less than three bleeding and/or spotting episodes in 90 days (excluding amenorrhea)||33.6|
|Amenorrhea ||No bleeding and/or spotting in 90 days||22.2|
|Prolonged ||Any bleeding and/or spotting episode lasting more than 14 days in 90 days||17.7|
|Frequent||More than 5 bleeding and/or spotting episodes in 90 days||6.7|
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.
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.
There have been postmarketing 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.
B. WARNINGS BASED ON EXPERIENCE WITH COMBINATION (PROGESTIN PLUS ESTROGEN) ORAL CONTRACEPTIVES
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 the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes.
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 advised not to smoke.
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.
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 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.
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.
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.
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™ (etonogestrel implant).
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.
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.
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.
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.
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.
Women with a history of depression should be carefully observed. Consideration should be given to removing IMPLANON™ in patients who become significantly depressed.
8. Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
9. Drug Interactions
Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Drugs
a. Anti-Infective Agents and Anticonvulsants
IMPLANON™ is not recommended for women who require chronic use of drugs that are potent inducers of hepatic enzymes because IMPLANON™ is likely to be less effective for these women.
Contraceptive effectiveness may be reduced when hormonal contraceptives are co- administered with some antibiotics, antifungals, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in an unintended pregnancy or breakthrough bleeding. Examples include barbiturates, griseofulvin, rifampin, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, and modafinil. Patients should use an additional nonhormonal contraceptive method when taking medications that may decrease the efficacy of hormonal contraceptives.
b. Anti-HIV Protease Inhibitors
Several of the anti-HIV protease inhibitors have been studied with co-administration of combination oral contraceptives; significant changes (increase and decrease) in the mean area under the curve (AUC) of the estrogen and progestin have been noted in some cases. The efficacy and safety of combination oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors; it is unknown whether this applies to IMPLANON™. Healthcare providers should refer to the labeling of the individual anti-HIV protease inhibitors for further drug-drug interaction information.
c. Herbal Products
Herbal products containing St. John's Wort (Hypericum perforatum) may induce hepatic enzymes and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids.
Increase in Plasma Hormone Levels Associated with Co-Administered Drugs
Inhibitors of hepatic enzymes such as itraconazole or ketoconazole may increase plasma hormone levels.
10. Interactions with Laboratory Tests
Certain endocrine tests may be affected by IMPLANON™ use:
a. Sex hormone-binding globulin concentrations may be decreased for the first six months after IMPLANON™ insertion followed by a gradual recovery.
b. Thyroxine concentrations may initially be slightly decreased followed by gradual recovery to baseline.
11. Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 24-month carcinogenicity study in rats with subdermal implants releasing 10 and 20 µg 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.
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.
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 professionals should discuss both hormonal and non-hormonal contraceptive options, as steroids may not be the initial choice for these patients.
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.
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.
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.
17. Geriatric Use
This product has not been studied in women over 65 years of age and is not indicated in this population.