"The U.S. Food and Drug Administration today announced that it has approved an amended application submitted by Teva Women's Health, Inc. to market Plan B One-Step (active ingredient levonorgestrel) for use without a prescription by women 15 years"...
Warnings Based on Experience with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM
Insertion and Removal Complications
A surgical incision is required to insert NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules. Complications related to insertion such as pain, edema, and bruising may occur. There also have been reports of infection (including cellulitis and abscess formation), blistering, ulcerations, sloughing, excessive scarring, phlebitis, and hyperpigmentation at the insertion site. There have been reports of arm pain, numbness, and tingling following the insertion and removal procedures. There also have been reports of nerve injury, most commonly associated with deep placement and removal. Expulsion of capsules has been reported more frequently when placement of the capsules was shallow or too close to the incision or when infection was present. There have been reports of capsule displacement (i.e., movement), most of which involved minor changes in the positioning of the capsules. However, infrequent reports ( < 1%) of significant displacement (a few to several inches) have been received. Some of these reports 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 locating capsules. These complications may lead to the need for additional incisions and/or office visits. See also “PRECAUTIONS” and “ADVERSE REACTIONS.”
Most women can expect some variation in menstrual bleeding patterns. Irregular menstrual bleeding, intermenstrual spotting, prolonged episodes of bleeding and spotting, heavy bleeding, and amenorrhea occur in some women. Irregular bleeding patterns associated with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM could mask symptoms of cervical or endometrial cancer. Overall, these irregularities diminish with continuing use. Since some NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users experience 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 capsules must be removed.
Although bleeding irregularities have occurred in clinical trials, proportionately more women had increases rather than decreases in hemoglobin concentrations, a difference that was highly statistically significant. This finding generally indicates that reduced menstrual blood loss is associated with the use of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, although some patients experience heavy bleeding that results in hemoglobin values consistent with anemia.
Ovarian Cysts (Delayed Follicular Atresia)
If follicular development occurs with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, atresia of the follicle is sometimes delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle. These enlarged follicles cannot be distinguished clinically from ovarian cysts. In the majority of women, enlarged follicles will spontaneously disappear and should not require surgery. Rarely, they may twist or rupture, sometimes causing abdominal pain, and surgical intervention may be required.
Ectopic pregnancies have occurred among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users, although clinical studies have shown no increase in the rate of ectopic pregnancies per year among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users as compared with users of no method or of IUDs. The incidence among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users was 1.3 per 1000 woman-years, a rate significantly below the rate that has been estimated for noncontraceptive users in the United States (2.7 to 3.0 per 1000 woman-years); however, any pregnancy that does occur in a woman using Norplant (levonorgestrel implants (unavailable in us)) is more likely to be ectopic than a pregnancy in a woman using no contraceptive at all. The risk of ectopic pregnancy may increase with the duration of NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use and possibly with increased weight of the user. Health-care professionals should be alert to the possibility of an ectopic pregnancy among women using the NORPLANT SYSTEM (levonorgestrel implants) who become pregnant or complain of lower-abdominal pain. Any patient who presents with lower-abdominal pain must be evaluated to rule out ectopic pregnancy.
Rarely, cancers have occurred at the site of foreign-body intrusions or old scars. None has been reported in NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM clinical trials. 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 capsules, the risk to users of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM is judged to be minimal.
Thromboembolic Disorders and Other Vascular Problems
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. There have also been post-marketing reports of these events coincident with NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use. The reports of thrombophlebitis and superficial phlebitis have more commonly occurred in the arm of insertion. Some of these cases have been associated with trauma to that arm.
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, while smoking interacted to increase the risk for hemorrhagic strokes. There have been post-marketing reports of stroke coincident with NORPLANT SYSTEM (levonorgestrel implants) use.
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. There have been post-marketing reports of myocardial infarction coincident with NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use.
Patients who develop active thrombophlebitis or thromboembolic disease should have the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules removed. Removal should also be considered in women who will be subjected to prolonged immobilization due to surgery or other illnesses.
Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. There is no evidence suggesting that the risk associated with NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use is different.
There have been rare reports of congenital anomalies in offspring of women who were using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM inadvertently during early pregnancy. A cause and effect relationship is not believed to exist.
Idiopathic Intracranial Hypertension
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. There have been reports of idiopathic intracranial hypertension in NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users. A cardinal sign of idiopathic intracranial hypertension is papilledema; early symptoms may include headache (associated with a change in frequency, pattern, severity, or persistence; of particular importance are those headaches that are unremitting in nature) and visual disturbances. 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. NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM should be removed from patients experiencing this disorder.
Warnings Based on Experience with Combination (Progestin plus Estrogen) Oral Contraceptives
Cigarette smoking increases the risk of serious cardiovascular side effects from the use of combination oral contraceptives. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with a significantly increased risk) and is quite marked in women over 35 years old. 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 the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM; however, women who use the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM should be advised not to smoke.
Elevated Blood Pressure
Increased blood pressure has been reported in users of combination oral contraceptives. The prevalence of elevated blood pressure increases with long exposure. Although there were no statistically significant trends among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users in clinical trials, health-care professionals should be aware of the possibility of elevated blood pressure with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM.
Carcinoma of the Breast and Reproductive Organs
Numerous epidemiological studies have examined the association between the use of oral contraceptives and the incidence of breast and cervical cancer.
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 combination oral contraceptive discontinuation and by 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 reported a small increase in risk with combination oral contraceptives first used at a younger age. 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.
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 hormonally-sensitive tumor.
Some studies suggest that combination oral-contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer 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 of the relationship between combination oral-contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established.
Evidence indicates that combination oral contraceptives may decrease the risk of ovarian and endometrial cancer. Irregular bleeding patterns associated with the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM could mask symptoms of cervical or endometrial cancer.
Hepatic adenomas have been found to be associated with the use of combination oral contraceptives with an estimated incidence of about 3 occurrences per 100,000 users per year, a risk that 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.
There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. Although it is believed that this adverse reaction is related to the estrogen component of oral contraceptives, the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules 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.
Earlier 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 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 hormonal doses of estrogens and progestins. The association of this risk with the use of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM progestin-only method is not known.
Patients should be counseled that this product does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
Physical Examination and Follow-Up
A complete medical history and physical examination should be taken prior to the implantation or reimplantation of NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules and at least annually during its 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.
Insertion and Removal
To be sure that the woman is not pregnant at the time of capsule 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 an abortion. However, NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules may be inserted at any time during the cycle provided pregnancy has been excluded and the possibility that ovulation and conception have already occurred has been considered. Insertion is not recommended before 6 weeks postpartum in breast-feeding women.
Insertion and removal instructions must be followed closely. It is strongly advised that all health-care professionals who insert and remove NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules be instructed in the procedures before they attempt them. Proper insertion just under the skin will facilitate removal.
If infection develops after insertion, suitable treatment should be instituted. If infection persists, capsules should be removed.
In the case of capsule expulsion, the expelled capsule must be replaced using a new sterile capsule, as contraceptive efficacy may be inadequate with fewer than six capsules. If infection is present, it should be treated and cured before capsule replacement.
Removal should be done upon patient request, for medical indications, or at the end of 5 years of use, by personnel instructed in the removal technique. If the capsules were placed deeply, they may be harder to remove. The use of general anesthesia during removal should generally be avoided.
Before initiating the removal procedure, all NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules should be located via palpation. If all six capsules cannot be located by palpation, they may be localized by ultrasound (7 MHz), X-ray, or compression mammography. If all capsules cannot be removed at the first attempt, removal should be attempted later when the site has healed.
Upon removal, NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules should be disposed of in accordance with the Centers for Disease Control and Prevention guidelines for the handling of biohazardous waste.
Carbohydrate and Lipid Metabolism
An altered glucose tolerance characterized by decreased insulin sensitivity following glucose loading has been found in some users of combination and progestin-only oral contraceptives. The effects of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM on carbohydrate metabolism appear to be minimal. In a study in which pretreatment serum-glucose levels were compared with levels after 1 and 2 years of NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use, no statistically significant differences in mean serum-glucose levels were evident 2 hours after glucose loading. The clinical significance of these findings is unknown, but diabetic patients should be carefully observed while using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM.
Women who are being treated for hyperlipidemias should be followed closely if they elect to use the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM. Some progestins may elevate LDL levels and may render the control of hyperlipidemias more difficult. (See “WARNINGS,” A. 6.)
If jaundice develops in any women while using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, consideration should be given to removing the capsules. 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 which might be aggravated by fluid retention.
Some cases of depression (including severe depression) have been reported in NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users, although clinical studies have not demonstrated differences in the risk of depression among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users when compared with users of other hormonal contraceptives. Health-care professionals should be alert to the possibility that depression might be related to NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM use, and consideration should be given to removing NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM capsules in women who become significantly depressed. 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 NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users; however, the rate of reporting is significantly less than the expected incidence 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 disease among NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM users is coincidental, health-care professionals should be alert to the earliest manifestations.
See “WARNINGS” section.
Pregnancy Category X. See “WARNINGS” section.
Steroids are not considered the contraceptives of first choice for breast-feeding women. Levonorgestrel has been identified in the breast milk. The health of breast-fed infants whose mothers began using the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM during the 5th to 7th week postpartum was evaluated; no significant effects were observed on the growth or development of infants who were followed to 12 months of age. No data are available on use in breast-feeding mothers earlier than this after parturition.
Safety and efficacy of the NORPLANT SYSTEM (levonorgestrel implants) have been established in women of reproductive age. Safety and efficacy are expected to be similar for postpubertal adolescents under 16 and users 16 and older. Use of this product before menarche is not indicated.
Information for the Patient
See Patient Labeling.
Two copies of the Patient Labeling are included to help describe the characteristics of the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM to the patient. 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 the NORPLANT (levonorgestrel implants (unavailable in us)) SYSTEM, with 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 professionals may wish to obtain informed consent from all patients in light of the techniques involved with insertion and removal.
Last reviewed on RxList: 1/5/2009
This monograph has been modified to include the generic and brand name in many instances.
Additional Norplant Information
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