Warnings

WARNINGS BASED ON EXPERIENCE WITH IMPLANON^® (etonogestrel implant) AND OTHER PROGESTIN-ONLY CONTRACEPTIVES

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.

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.

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.

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 two years, and the proportion of 90-day intervals with these bleeding patterns, are summarized in the following table.

% = Percentage of 90-day intervals with this pattern
Based on 3315 recording periods of 90 days duration in 780 women, excluding the first 90 days after implant insertion

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.
 
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.

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 and estrogen) oral contraceptives.

WARNINGS BASED ON EXPERIENCE WITH COMBINATION (PROGESTIN PLUS ESTROGEN) ORAL CONTRACEPTIVES

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.

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.

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. If 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.

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.

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 US and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

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.