A. WARNINGS BASED ON EXPERIENCE WITH LEVONORGESTREL-CONTAINING IMPLANTS

A surgical incision is required to insert JadelleÃ? implants. Complications related to insertion such as pain, edema and bruising may occur. Reports of infection (including cellulitis and abscess formation), blistering, ulcerations, sloughing, excessive scarring, phlebitis and hyperpigmentation have been reported at the insertion site for the six NORPLANTÃ? implants and may occur with JadelleÃ? implants. Arm pain, numbness and tingling may occur following the insertion and removal procedures. With NORPLANTÃ? implants, there have been reports of nerve injury, most commonly associated with deep placement and removal. Expulsion of 1 or more NORPLANTÃ? implants has been reported, more frequently when implant placement was shallow or too close to the incision or when infection was present. There have been reports of displacement (i.e. movement) of NORPLANTÃ? implants, most of which involved minor changes in the positioning of the implants, but some have involved significant displacement of up to several inches. Some of these reported displacements have been associated with pain and difficult removal. Removal is also a surgical procedure and may take longer, be more difficult and/or cause more pain than insertion and may be associated with difficulty in locating implants. Additional incisions and/or office visits may be required. See also "PRECAUTIONS" and "ADVERSE REACTIONS".

Physicians should be alert to the possibility of an ectopic pregnancy among women using JadelleÃ? implants who become pregnant or complain of lower abdominal pain. Ectopic pregnancies occurred with JadelleÃ? implants at a rate less than 0.5 per 1,000 woman-years. This rate is significantly below the rate for US women of reproductive age who do not use contraception, which is 2.7 to 3.0 per 1,000 woman-years. However, any pregnancy that does occur with JadelleÃ? use is more likely to be ectopic than a pregnancy occurring in a woman using no contraception.

JadelleÃ? implants are not recommended for women with epilepsy who use phenytoin, phenobarbital, carbamazepine or oxcarbazepine because JadelleÃ? implants are likely to be less effective for these women. Although the large clinical trials of NORPLANTÃ? and JadelleÃ? implants excluded women with epilepsy, there are published studies showing decreased levonorgestrel concentrations in women using these antiepileptic drugs along with levonorgestrel-containing contraceptives.

Women using rifampin have become pregnant during clinical trials of NORPLANTÃ? implants. Rifampin decreases serum levels of progestins. (See also DRUG INTERACTIONS.)

Most women using JadelleÃ? implants can expect some variation in menstrual bleeding patterns. Irregular menstrual bleeding, prolonged episodes of bleeding and spotting, heavy bleeding, intermenstrual spotting and amenorrhea occur in some women. Altered bleeding patterns associated with JadelleÃ? implants could mask symptoms of cervical or endometrial cancer. See also ADVERSE REACTIONS, Menstrual Complaints.

Because some levonorgestrel implant users have periods of amenorrhea, missed menstrual periods cannot serve as the only means of identifying early pregnancy. Pregnancy tests should be performed whenever a pregnancy is suspected. Six (6) weeks or more of amenorrhea after a pattern of regular menses may signal pregnancy. If pregnancy occurs, the implants must be removed.

In clinical trials of JadelleÃ? use, the average weight change over 5 years of use was a gain of about 9 pounds. Approximately 20% of women gained at least 10 pounds in the first year, and 50% gained at least 10 pounds by the end of the fifth year of use.

If follicular development occurs with JadelleÃ? implants, atresia of the follicle may be delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle. In the majority of women, enlarged follicles (cysts) will spontaneously disappear and should not require surgery. Rarely, they may twist or rupture, sometimes causing abdominal pain, and surgical intervention may be required.

Rarely, cancers have occurred at the site of foreign-body intrusions or old scars. None have been reported in NORPLANTÃ? users or in clinical trials with JadelleÃ? implants. In rodents, which are highly susceptible to such cancers, the incidence decreases with decreasing size of the foreign body. Because of the resistance of human beings to these cancers and because of the small size of the implants, the risk to users of JadelleÃ? implants is judged to be minimal.

There have been reports of superficial phlebitis in clinical trials of JadelleÃ? implant and postmarketing reports of thrombophlebitis and superficial phlebitis coincident with NORPLANTÃ? implant use, more commonly in the arm of insertion. Some of these cases have been associated with trauma to that arm. There have also been reports of other thromboembolic disorders and cardiovascular problems (eg, stroke, myocardial infarction, pulmonary embolism, and deep-vein thrombosis) coincident with NORPLANTÃ? implant use. See also WARNINGS BASED ON EXPERIENCE WITH COMBINATION (PROGESTIN PLUS ESTROGEN) ORAL CONTRACEPTIVES.

There were no reports of congenital anomalies for the pregnancies that occurred during use of JadelleÃ? implants in clinical trials. However, in postmarketing use of the NORPLANTÃ? implants, there have been reports of congenital anomalies in the offspring of women who were using NORPLANTÃ? implants inadvertently during early pregnancy. A cause and effect relationship has not been established. See also WARNINGS BASED ON EXPERIENCE WITH COMBINATION (PROGESTIN PLUS ESTROGEN) ORAL CONTRACEPTIVES.

Idiopathic intracranial hypertension (pseudotumor cerebri, benign intracranial hypertension) is a disorder of unknown etiology, which is seen most commonly in obese females of reproductive age. It has been reported in NORPLANTÃ? implant users; however, a causal relationship is unclear. A cardinal sign of idiopathic intracranial hypertension is papilledema; early symptoms may include headache associated with a change in the frequency, pattern, severity, or persistence. Of particular importance are visual disturbances and headaches that are unremitting in nature. Patients with these symptoms, particularly obese patients or those with recent weight gain, should be screened for papilledema and, if present, the patient should be referred to a neurologist for further diagnosis and care. JadelleÃ? implants should be removed from patients experiencing this disorder.

Thromboembolic and Thrombotic Disease: An increased risk of thromboembolic and thrombotic disease (pulmonary embolism, superficial venous thrombosis, and deep-vein thrombosis) has been found to be associated with the use of combination oral contraceptives. The relative risk has been estimated to be 4- to 11-fold higher for users than for nonusers.

Cerebrovascular Disorders: Combination oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although in general the risk is greatest among older (> 35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers for both types of strokes, and smoking interacted to increase the risk for hemorrhagic strokes.

Myocardial Infarction: An increased risk of myocardial infarction has been attributed to combination oral contraceptive use. This is thought to be primarily thrombotic in origin and is related to the estrogen component of combination oral contraceptives. This increased risk occurs primarily in smokers or in women with other underlying risk factors for coronary artery disease, such as family history of coronary artery disease, hypertension, hypercholesterolemia, morbid obesity, and diabetes. The current relative risk of heart attack for combination oral contraceptive users has been estimated as 2 to 6 times the risk for nonusers. The absolute risk is very low for women under 30 years of age.

Studies indicate a significant trend toward higher rates of myocardial infarctions and strokes with increasing doses of progestin in combination oral contraceptives. However, a recent study showed no increased risk of myocardial infarction associated with the past use of levonorgestrel-containing combination oral contraceptives.

If thromboembolic disorders or cardiovascular problems occur in levonorgestrel implant users, the implants should be removed. Removal should also be considered in women who will be subjected to prolonged immobilization because of surgery or other illnesses. See also WARNINGS BASED ON EXPERIENCE WITH LEVONORGESTREL-CONTAINING IMPLANTS.

Cigarette smoking increases the risk of serious cardiovascular side effects from the use of combination oral 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 such as JadelleÃ? implants. However, women who use JadelleÃ? implants should be advised not to smoke.

Increased blood pressure has been reported in users of combination oral contraceptives. The prevalence of elevated blood pressure increases with long exposure. Physicians should be aware of the possibility of elevated blood pressure in individual patients using JadelleÃ? implants.

Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives before pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb-reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. There is no evidence suggesting that the risk associated with levonorgestrel-containing implants is different from that of oral contraceptives. See also WARNINGS BASED ON EXPERIENCE WITH LEVONORGESTREL-CONTAINING IMPLANTS.

Numerous epidemiologic studies have been performed to determine the incidence of breast, endometrial, ovarian, and cervical cancer in women using combination oral contraceptives. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However this excess risk appears to decrease over time after discontinuation of combination oral contraceptives, and by 10 years after cessation the increased risk disappears. The risk does not appear to increase with duration of use, and no consistent relationships have been found with dose or type of steroid. Most studies show a similar pattern of risk with combination oral contraceptive use regardless of a womans reproductive history or her family breast cancer history. Some studies have found a small increase in risk for women who first use combination oral contraceptives before age 20. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in nonusers. Women who currently have or have had breast cancer should not use hormonal contraceptives because breast cancer is usually a hormone-sensitive tumor.

Some studies suggest that combination oral contraceptive use is associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. There continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. Despite the many studies of the relationship between combination oral contraceptive use and cervical cancers, a cause-and-effect relationship has not been established.

In some studies, hepatic adenomas have been associated with the use of combination oral contraceptives: the estimated incidence is about 3 occurrences per 100,000 users per year, and the risk increases after 4 or more years of use. Although benign, hepatic adenomas may rupture and cause death through intra-abdominal hemorrhage. The contribution of the progestin component of oral contraceptives to the development of hepatic adenomas is not known.

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.

There have been reports of retinal thrombosis associated with the use of oral contraceptives. Although it is believed that this adverse reaction is related to the estrogen component of oral contraceptives, JadelleÃ? implants should be removed if there is unexplained partial or complete loss of vision, onset of proptosis or diplopia, papilledema, or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

Some studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative increased risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower doses of estrogens and progestins.

A complete medical history and physical examination should be undertaken before the implantation or reimplantation of Jadelle implants and at least annually during their use.

These physical examinations should include special reference to the implant site, blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate diagnostic measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

To ensure that the woman is not pregnant at the time of implant placement and to assure contraceptive effectiveness during the first cycle of use, it is advisable that insertion be done during the first 7 days of the menstrual cycle or immediately following abortion. However, JadelleÃ? implants may be inserted at any other time during the cycle, provided that the possibility of ovulation and conception prior to insertion is considered, pregnancy has been excluded, and a nonhormonal contraceptive method is used for at least 7 days following implant placement. If ovulation and conception have already occurred, pregnancy may be established in the month of insertion.

It is strongly advised that all health-care professionals who insert and remove JadelleÃ? implants be instructed in the procedures before they attempt them. A proper insertion just under the skin will facilitate removal. Proper insertion and removal should result in minimal scarring. If the implants are placed too deep, they may be more difficult to remove.

Bruising may occur at the implant site during insertion or removal. There have also been reports of arm pain, numbness, and tingling following these procedures. In some women, hyperpigmentation occurs over the implantation site but it is usually reversible following removal. During postmarketing use of NORPLANTÃ? implants, other cutaneous reactions that have been reported include blistering, ulcerations, and sloughing. See the detailed "Instructions for Insertion and Removal" section below.

Infection at the implant site, including cellulitis, has been uncommon. During clinical trials with the JadelleÃ? implants, infection at the insertion site occurred in 0.4% of women Attention to aseptic technique and proper insertion and removal of JadelleÃ? implants reduces the possibility of infection. If infection occurs, suitable treatment should be instituted. If infection persists, the implants should be removed.

Expulsion of one or both implants is uncommon. It is more likely to occur when placement of the implants is extremely shallow, too close to the incision, or when infection is present. An expelled implant must be replaced with a new sterile implant. If infection is present, it should be resolved before another implant is inserted. Protection against pregnancy is likely to be inadequate with fewer than two implants.

There have been reports of implant displacement (i.e., movement) with NORPLANTÃ? implants, most of which involve minor changes in the position of the implants. However, infrequent reports of significant displacement (up to several inches) have been received. Some instances of displacement have been associated with pain or discomfort. When implant displacement occurs, the removal technique may have to be modified, for example, by an additional incision or visit.

Women should be advised that JadelleÃ? implants can be removed for any reason whenever the woman wishes and must be removed by the end of five years. The removal should be done by personnel familiar with the removal techniques.

Before initiation of the removal procedure, the two JadelleÃ? implants should be located by palpation. If both implants cannot be located by palpation, they may be localized by ultrasound (7 MHz), X-ray, or compression mammography. If both implants cannot be removed at the first attempt, removal should be attempted later when the site has healed.

Upon removal, JadelleÃ? implants should be disposed of in accordance with the Centers for Disease Control and Prevention guidelines for the handling of biohazardous waste.

Serum lipoprotein levels were altered in three clinical studies involving 544 women using Jadelle implants. Although these changes were statistically significant, all mean values remained within the normal ranges. The long-term clinical effects of these changes have not been determined.

Women who are being treated for hyperlipidemias should be followed closely if they elect to use JadelleÃ? implants.

Changes in carbohydrate tolerance and insulin sensitivity following oral glucose loads have been reported in some studies among users of NORPLANTÃ? implants and of JadelleÃ? implants. These changes include modest elevations of serum insulin concentrations as well as increases in serum glucose levels. These changes were not associated with development of clinical or laboratory evidence of diabetes mellitus. While the clinical significance of these findings is unknown, diabetic patients should be carefully observed while using JadelleÃ? implants.

If jaundice develops in any woman using JadelleÃ? implants, consideration should be given to removing the implants. Steroid hormones may be poorly metabolized in patients with impaired liver function.

Steroid contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring in patients with conditions that cause or might be aggravated by fluid retention.

Consideration should be given to removing JadelleÃ? implants in women who become significantly depressed, because depression may be drug related. Women with a history of depression should be carefully observed, and removal considered if depression recurs to a serious degree.

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

Autoimmune diseases such as scleroderma, systemic lupus erythematosus, and rheumatoid arthritis occur in the general population and more frequently among women of childbearing age. There have been rare reports of various autoimmune diseases, including the above, in NORPLANTÃ? implant users; however, the rate of reporting is significantly lower than the expected incidences for these diseases. Studies have raised the possibility of developing antibodies against silicone-containing devices; however, the specificity and clinical relevance of these antibodies are unknown. While it is believed that the occurrence of autoimmune diseases among NORPLANTÃ? implant users is coincidental, health-care providers should be alert to the earliest manifestations of autoimmune disease in users of JadelleÃ? implants.

Certain endocrine tests may be affected by JadelleÃ? use:

1. SHBG concentrations are decreased.

2. Thyroxine concentrations may be slightly decreased and triiodothyronine uptake increased.

See "WARNINGS" section.

See "WARNINGS" section.

15. Nursing Mothers

Hormonal contraceptives are not considered the contraceptives of first choice for breast-feeding women. Levonorgestrel has been identified in breast milk. When breast-feeding mothers used NORPLANTÃ? implants beginning during the 5^th to 7^th week postpartum, no significant effects were observed on the growth or development of their infants who were followed up to 12 months of age.

Safety and efficacy of JadelleÃ? implants have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

This product has not been studied in women over 65 years of age and is not indicated in this population.

18. Information for the Patient

See "Patient Labeling."

Two copies of the Patient Labeling are included. One copy should be provided to the patient. Patients should also be advised that the Prescribing Information is available to them at their request. It is recommended that prospective users be fully informed about the risks and benefits associated with the use of JadelleÃ? implants compared to other forms of contraception, and with no contraception at all. It is also recommended that prospective users be fully informed about the insertion and removal procedures. Health-care providers may wish to obtain informed consent from all patients in light of the techniques involved with insertion and removal.

Bookmark this page: