Common adverse reactions associated with levonorgestrel used orally as an emergency contraceptive (e.g., Plan-B) are usually self-limited to the treatment period. Nausea occurs in 13% to 23% and vomiting in 5.6% of patients versus 51% and 19%, respectively, of those who take estrogen-progestin oral emergency contraceptives (e.g., the Yuzpe methods). Other common side effects include abdominal pain (13% to 18%), fatigue (13% to 17%), and dizziness (9% to 11%). Serious side effects are not common.[33117] [52930] In Mirena levonorgestrel intrauterine device (IUD) trials, adverse events reported in Mirena users included abdominal pain (5%), nausea (5%), and vomiting (less than 5%). Weight gain was reported in 9% of Mirena users in a study of women who have used Mirena for more than 5 years; it is unknown if the weight gain was attributed to Mirena use.[48254] In Skyla levonorgestrel IUD trials, abdominal pain (18.9%) and nausea (5.5%) were reported.[52878] In Liletta levonorgestrel IUD trials, nausea or vomiting (10.5%), abdominal discomfort or pain (10%), and weight gain (6.1%) were reported.[58928] In Kyleena levonorgestrel IUD trials, abdominal pain was reported in 13.3 to 21% of patients and was the cause for study discontinuation in 4.2% of patients. Nausea was reported in 4.7% of Kyleena IUD users.[61277] Any patient using a levonorgestrel IUD should report continued or severe pelvic or abdominal pain or nausea/vomiting, as these may be symptoms of pregnancy, infectious processes, device embedment, or a cyst that may need medical evaluation or treatment.

Because levonorgestrel in the intrauterine device (IUD) system is released just within the uterus, very few systemic side effects are expected to occur. Serious, but rare, adverse events associated with the device include IUD system embedment causing cervical or uterine perforation. The incidence of uterine perforation during clinical trials of the various levonorgestrel IUDs, which excluded breast-feeding women, was less than 0.1%.[48254] [52878] [58928] [61277] Data from a large postmarketing safety study suggest an increased risk of uterine perforation in lactating women; the incidence of uterine perforation was reported as 6.3 per 1,000 insertions for lactating women, compared to 1 per 1,000 insertions for non-lactating women.[61655] [61656] In a large retrospective cohort study, women who were breast-feeding at the time of IUD insertion were at a 33% higher risk of uterine perforation compared to women who were not breast-feeding at the time of insertion. The risk of perforation was highest with IUD insertion in the period up to 6 weeks postpartum. Progressively lower risk of uterine perforation was observed in the postpartum insertion time window beyond 6 weeks.[48254] [52878] [61277] The risk may be increased if an IUD is inserted when the uterus is fixed retroverted or not completely involuted. Most manufacturers recommend waiting a minimum of 6 weeks postpartum for uterine involution to minimize the risk; some experts state anytime 4 weeks or more postpartum may be acceptable but specific device recommendations should be consulted.[48201] [48254] [52878] [58928] [61277] Penetration of the uterine wall or cervix may also occur during any IUD insertion procedure, although the perforation may not be detected immediately. If embedment occurs, the IUD should be removed as contraceptive efficacy is decreased; surgery may be required. If perforation occurs, pregnancy may occur; the IUD must be removed as soon as possible and surgery may be required. Delayed identification of uterine perforation may lead to migration of the IUD outside of the uterine cavity, adhesions, peritonitis, intestinal perforations, intestinal obstruction, and abscesses and erosion of adjacent viscera. Device breakage has also been reported during postmarketing experience with the various levonorgestrel IUDs and requires removal of the broken device.[48254] [52878] [58928] [61277] There is also a risk for IUD expulsion during use. Partial or complete expulsion of a levonorgestrel IUD may occur, resulting in the loss of contraceptive protection. IUD expulsion may be associated with symptoms of bleeding or pain, or it may be asymptomatic and go unnoticed. An increase in menstrual blood flow during use of a levonorgestrel IUD may also be indicative of device expulsion, since the levonorgestrel IUDs typically cause menstrual bleeding to decrease over time after insertion. Consider further diagnostic imaging, such as x-ray, if IUD expulsion is suspected based on ultrasound. If IUD threads are not visible, consider the possibility of retraction or expulsion. In clinical trials for the Mirena levonorgestrel IUD, a 4.5% expulsion rate was reported over the 5-year study duration. In clinical trials for Skyla levonorgestrel IUD, a 3-year expulsion rate of 3.2% (54 out of 1,665 subjects) was reported. In the clinical trial for contraception with Liletta levonorgestrel IUD, an overall expulsion rate of 4.1% was reported, with a rate of 2.4% in nulliparous women and 6.4% in parous women. Risk of expulsion may be increased with patients with heavy menstrual bleeding or greater than normal BMI and treatment with Liletta. During clinical trials for heavy menstrual bleeding, 8.6% of patients receiving Liletta experienced expulsions, with two-thirds occurring within the first 90 days. About 90% of the expulsions occurred in overweight or obese patients. In Kyleena levonorgestrel IUD trials, a 5-year expulsion rate of 3.5% (59 out of 1,690 subjects) was reported and was the cause for study discontinuation in 3.1% of patients. If expulsion occurs, levonorgestrel IUDs may be replaced any time the provider can be reasonably certain the woman is not pregnant.[48254] [52878] [58928] [61277] Data from a large postmarketing safety study suggest risk of IUD expulsion was variable over the postpartum interval through 52 weeks. Patients who were breast-feeding were at a 28% lower risk of IUD expulsion compared to those who were not breast-feeding at the time of insertion.[48254] [52878] [61277]

In levonorgestrel intrauterine device (IUD) trials, ectopic pregnancy was reported among serious adverse reactions. The incidence of ectopic pregnancy in clinical trials with levonorgestrel IUDs was approximately 0.1% to 0.2% per year. In patients without risk factors, ectopic pregnancy is an infrequent complication of levonorgestrel IUD users (rate of 1 per 1,000 users per year). However, up to 50% of pregnancies that occur when an IUD is already in place may be ectopic. The risk of an ectopic pregnancy in women who have a history of ectopic pregnancy is not known; clinical trials excluded patients with a history of ectopic pregnancy, and use in this population is not recommended.[48254] [52878] [58928] [61277]

Common adverse reactions associated with levonorgestrel used orally as an emergency contraceptive (e.g., Plan-B) include menstrual changes [heavier (13% to 30%) or lighter bleeding (13%)], and breast tenderness (8% to 11%). A pregnancy test is indicated if menstrual bleeding does not occur within 21 days of taking the emergency oral levonorgestrel regimen; serious side effects are not common.[52930] In Mirena levonorgestrel intrauterine device (IUD) trials, adverse events reported in 5% of Mirena users include: dysmenorrhea (6.4%); mastalgia (8.5%); leukorrhea; libido decrease. Vulvo-vaginitis was reported in 10.5%.[48254] In Skyla levonorgestrel IUD trials, common adverse reactions (occurring in at least 5% of users) included: increased menstrual bleeding or menorrhagia (7.8%); vulvo-vaginitis (20.2%); dysmenorrhea (8.6%); breast pain/discomfort (mastalgia) (8.6%).[52878] In Liletta levonorgestrel IUD trials, common reported adverse reactions (occurring in at least 5% of users) included: breast tenderness or pain (mastalgia) (10.1%) and dysmenorrhea (7.3%).[58928] Increased menstrual bleeding (menorrhagia) was reported in 8% of women using Kyleena and was the cause for discontinuation in 4.5 % of patients. Dysmenorrhea (8% to 10%) and uterine spasm (2.4% to 10%) were reported in Kyleena users and were rarely cause for discontinuation. Mastalgia (7.1% to 10%) or breast discomfort (3.5% to 10%), and vulvo-vaginitis (24%) were also reported with Kyleena.[61277] It is common/expected for levonorgestrel IUDs to alter the menstrual bleeding pattern and result in menstrual irregularity, spotting or breakthrough bleeding, heavy bleeding, oligomenorrhea, and amenorrhea. During the first 3 to 6 months of IUD use, the number of bleeding and spotting days may be increased and bleeding patterns may be irregular. After that, the number of bleeding and spotting days usually decreases, but bleeding may remain irregular. If bleeding irregularities develop during prolonged treatment, appropriate diagnostic measures should be taken to rule out endometrial pathology. Amenorrhea develops in approximately 20% of Mirena users by end of year 1. By the end of year 8, amenorrhea and infrequent bleeding occur in 34% and 26% of patients, respectively; irregular bleeding occurs in 10%, frequent bleeding in 3%, and prolonged bleeding in 3% of users.[48254] Amenorrhea develops in approximately 6% of Skyla users by the end of year 1 and 12% by the end of year 2.[52878] Amenorrhea developed in approximately 19% of Liletta users by the end of year 1, in 27% by the end of year 2, in 37% of users by the end of year 3, 37% by the end of year 4, 40% by the end of years 5 and 6, and 39% by the end of years 7 and 8. During clinical trials in women with heavy menstrual bleeding, 19% of patients developed amenorrhea by the sixth 28-day cycle of Liletta. The number of spotting days increased from a baseline average of 1.8 days, to an average of 7.3 days by cycle 3, and 5.1 days by cycle 6. The number of bleeding days decreased from a baseline average of 4.9 days to 3.7 days by cycle 3, and 2.2 days by cycle 6. Treatment discontinuation due to bleeding complains occurred in 3.8% of patients treated with Liletta for heavy menstrual bleeding during clinical trials (n=87).[58928] Amenorrhea developed in approximately 12% of Kyleena users by the end of year 1, in 20% by the end of year 2, and in approximately 23% of users by the end of year 5.[61277] The possibility of pregnancy should be considered if menstruation does not occur within 6 weeks of the onset of previous menstruation in a woman with any of these IUDs. Once pregnancy has been excluded, repeated pregnancy tests are generally not necessary in amenorrheic women unless indicated, for example, by other signs of pregnancy/ectopic pregnancy. A levonorgestrel IUD should be removed for menorrhagia and/or metrorrhagia that produces anemia. In levonorgestrel IUD clinical trials, adverse events reported in 5% or less of patients included anemia.[48254] [52878] [58928] [61277]

Genital or vaginal discharge occurred in the following percentages of patients receiving the various levonorgestrel intrauterine devices (IUDs): Mirena 14.9%, Kyleena, 4.5%, Liletta 5.8%, and Skyla 4.2%. Dyspareunia was reported in less than 5% of patients (Mirena), in 9.6% of patients (Liletta), and was not specifically reported for Skyla or Kyleena but estimated at less than 1%. Pelvic pain has been reported in users of levonorgestrel IUDs in clinical trials: 22.6% for Mirena, 8.7% for Liletta, 6.2% to 18.9% for Skyla, and 8.2% to 21% for Kyleena.[48254] [52878] [58928] [61277] Uterine contractions, cramps, or spasms may occur in roughly 0.6% to 10% of levonorgestrel IUD users and are common upon device insertion; continuing uterine spasm can lead to IUD discontinuation in some patients.[48254] [52878] [58928] [61277] Since the contraceptive effect of the levonorgestrel IUD is mainly due to its local effect, ovulatory cycles with follicular rupture usually occur in women of fertile age, and sometimes atresia of the follicle is delayed and the follicle may continue to grow. Ovarian cyst or enlarged follicles (which may cause ovarian enlargement due to the size of the cyst) have been diagnosed sometime during IUD use in approximately 12% of those using Mirena IUD, 14% using Skyla IUD, and 22% using Kyleena IUD, and infrequently (less than 1%) in those using Liletta IUD. Ovarian cysts were reported as adverse events in 13.2% of women using Skyla IUD if they were abnormal, non-functional cysts and/or had a diameter more than 3 cm on ultrasound examination; 0.3% of women discontinued because of an ovarian cyst.[52878] Symptomatic ovarian cysts occurred in 4.7% of participants using Liletta IUD doe contraception over the course of 8 years, and 0.3% of patients discontinued use because of an ovarian cyst. During clinical studies in women with heavy menstrual bleeding, symptomatic ovarian cysts occurred in 1% of patients treated with Liletta over 6 months.[58928] Most of these follicles are asymptomatic, although some may be accompanied by dyspareunia. In most cases the enlarged follicles disappear spontaneously during the first 2 to 3 months observation. Surgical intervention is not usually required. Ovarian cysts can cause clinical symptoms including pelvic pain, abdominal pain or dyspareunia and a patient should contact her healthcare provider if she experiences these symptoms.[48254] [52878] [58928] [61277] In Liletta IUD clinical trials, vaginal bacterial infections (19.2%) and vulvovaginal mycotic infections (20.2%) were reported. Pelvic infection (0.2% to 3.5% of levonoregestrel IUD users) may occur and such upper genital tract infections may be serious. Endometritis (estimated incidence 0.2% to 2.1%) is an infection that may occur soon after IUD insertion. Severe infection or sepsis, including Group A streptococcal sepsis (GAS), have been reported immediately following insertion of levonorgestrel IUDs. In some cases, severe pelvic pain occurs within hours of insertion followed by sepsis within days. Because death from GAS is more likely if treatment is delayed, it is important to be aware of this rare but serious infection. Aseptic technique during IUD insertion is essential. Pelvic inflammatory disease (PID) has been reported with all IUD devices and the risk of subsequent infection is increased in those patients with a history of PID. The incidence of pelvic inflammatory disease is rare to infrequent, but is estimated from levonorgestrel IUD clinical trial data to be approximately 0.4% to 0.6% and most often occurs within the first year of use and often within the first month of insertion.[48254] [52878] [58928] [61277] Pelvic infections can cause tubal damage leading to ectopic pregnancy or infertility, or infrequently can necessitate hysterectomy, or cause death. Teach patients to recognize and report to their healthcare provider promptly any symptoms of pelvic infection. These symptoms include development of menstrual disorders (prolonged or heavy bleeding), unusual or odorous vaginal discharge, abdominal or pelvic pain or tenderness, dyspareunia, chills, and fever. Abdominal pain, pelvic pain, or dyspareunia in any user of a levonorgestrel intrauterine device (IUD) may need to prompt a clinical evaluation, to exclude infectious processes (e.g., sexually transmitted disease, endometritis or pelvic inflammatory disease), ovarian cysts, pregnancy, or other serious medical issues. An odorous vaginal discharge, or discharge accompanied by other symptoms, may indicate a need to rule out an infectious process. A levonorgestrel IUD should be removed for any of the following medical reasons: AIDS or other sexually transmitted disease, pelvic infection, endometritis, genital actinomycosis, intractable pelvic or uterine pain, severe dyspareunia, or uterine or cervical perforation.[48254] [52878] [58928] [61277]

Headache (9.8% to 17%) is a common side effect associated with levonorgestrel used orally as an emergency contraceptive (e.g., Plan-B) but is usually self-limited to the time around the treatment period.[33117] [52930] Headache and migraine are also reported in users of levonorgestrel intrauterine devices (IUDs). In Mirena IUD trials, headache/migraine was reported in 16.3% of Mirena users. In Skyla IUD trials headache was reported in 12.4%, migraine was reported in 2.3%. In Liletta IUD clinical trials, headache/migraine was reported in 10.1%. In Kyleena IUD trials headache (12.9% to 15%) and migraine (3.3% to 15%) were reported. As with all hormonal contraceptives, headache patterns may change during levonorgestrel use. Consider IUD removal if migraine headaches or exceptionally severe headaches occur, especially if the migraine is focal in nature with asymmetrical visual impairment or other symptoms that may suggest transient cerebral ischemia and risk for cerebrovascular accident (CVA).[48254] [52878] [58928] [61277]

Fluid retention may occur in patients receiving chronic therapy with progestins, including levonorgestrel intrauterine devices (IUDs), but has not been specifically reported with use. In Mirena levonorgestrel IUD trials, increased blood pressure was reported as an adverse event in 5% of users and was reported during postmarket experience with Kyleena. During use, if marked increased blood pressure or hypertension occurs, consider IUD discontinuation.[48254] [52930] [52878] [61277] Rare cases of arterial and venous thromboembolism, including cases of pulmonary embolism, deep vein thrombosis and stroke, have occurred during use of levonorgestrel IUDs postmarketing.[48254] [52930] [52878] [61277] Progestin-only contraceptives are generally the hormonal contraceptives of choice in patients with a potential risk for thrombosis when reliable contraception must be ensured and the risks of hormonal therapy are acceptable; advantages of these methods usually outweigh potential risks. When multiple thrombosis risk factors exist, the risk of thromboembolic disease may increase. The increase in the risk of thrombosis from newer progestin-only contraceptives (e.g., levonorgestrel IUD) is still substantially less than with combined oral contraceptives containing both estrogen and progestin. For women who are at an increased risk of thromboembolism and have multiple-risk factors for thrombosis (e.g., tobacco smoking woman age 35 and older, diabetes, hypercoagulopathy, severe hypertension, etc.), consider an IUD or other estrogen-free contraceptive if appropriate.[48201] A provider should be alert to the earliest manifestations of thrombotic disorder (thrombophlebitis, cerebrovascular disease, cardiac disease, myocardial infarction, pulmonary embolism, severe hypertension, stroke, valvular heart disease, and retinal thrombosis). Should any of these thrombotic-type events occur or be suspected, or if new risk factors warrant, consider removal of the levonorgestrel IUD.[48254] [52930] [52878] [61277] Patients using oral levonorgestrel are not expected to be at significant/clinical risk of thromboembolic complications due to short duration of use; the advantages of the emergency contraceptive usually outweigh any theoretical risks.[48201] [52930] [55077]

Dermatologic and allergic reactions have been reported in levonorgestrel intrauterine device (IUD) users. Acne vulgaris was reported in 6.8% of Mirena IUD users. Less than 5% of patients receiving Mirena IUD reported hirsutism and alopecia (partial and complete).[48254] In Liletta levonorgestrel IUD trials, acne vulgaris was reported in 15.5%.[58928] In Skyla IUD trials, acne vulgaris was reported in 13.6% and seborrhea in 1.4%.[52878] In Kyleena IUD trials, acne was reported in 14.1%, seborrhea in 1.8%, and alopecia was reported in 1%. Hypersensitivity reactions, including rash (unspecified), urticaria, and angioedema have been reported during postmarketing experience with the various levonorgestrel IUDs.[48254] [52878] [58928] [61277]

Patients receiving levonorgestrel intrauterine device (IUD) contraceptives can experience emotional lability. In Mirena IUD trials, depression or depressive mood were reported in 6.4%.[48254] In Liletta levonorgestrel IUD trials, anxiety (9.6%), depression or depressed mood (9.1%), and mood changes (6.5%) were reported. In Skyla IUD trials, depression (3.8%) and depressed mood (0.5%) were reported. In Kyleena IUD trials, depression (4.4%) and depressed mood (0.2%) were reported.[61277] Rarely serious psychiatric adverse reactions have been reported such as suicidality and exacerbations of depression and bipolar disorder.[58928]

Syncope, bradycardia, or other neurovascular episodes may occur during insertion or removal of the levonorgestrel intrauterine device (IUD), especially in patients predisposed to these conditions or with cervical stenosis. These side effects are due to the device procedures involved and not due to the drug itself. If decreased pulse, diaphoresis, or pallor is observed, the patient should remain supine until these signs have disappeared.[48254] [52930] [58928] [61277]

In levonorgestrel intrauterine device (IUD) clinical trials, back pain was reported in 0% to 7.9% of patients.[48254] [52878] [58928] [61277]

Rare adverse reactions that may occur with chronic administration of progestins such as levonorgestrel include hepatoma (benign or other tumor), elevated bilirubin levels, cholestasis, jaundice, and hyperglycemia.[51292] The appearance of jaundice may indicate the need to evaluate for hepatic disease and is a reason to consider levonorgestrel intrauterine device (IUD) discontinuation.[48254] [52930] [52878] [61277]

The oral postcoital emergency contraceptive products (e.g., Plan B and others) are not to be used by females who suspect or know that they are pregnant.[52930] [55077] Plan B and Plan B One-Step are not effective for termination of an existing pregnancy. In the use of levonorgestrel for emergency contraception, the patient should be instructed to see her health care provider if there is a delay in the expected onset of menses beyond 1 week as a pregnancy test may be needed.[52930] [55077] Levonorgestrel intrauterine devices (IUDs) are contraindicated for use during pregnancy or suspected pregnancy.[48254] [52878] [58928] [61277] Prior to IUD insertion, exclude pregnancy (via pregnancy testing or other confirmation) and confirm that there are no other contraindications to the IUD insertion. Should an intrauterine pregnancy occur while an IUD is in place, the prescriber should refer to the specific IUD literature that states considerations during such events and the patient should be informed of the potential reproductive risks.[48254] [52878] [58928] [61277] The majority of recent studies do not indicate a teratogenic effect of progestin-only contraceptive IUDs when inadvertently used during early pregnancy; however, the IUD should be discontinued as soon as pregnancy is suspected or detected. When pregnancy continues with the IUD in place, long-term effects on the offspring are unknown. If an intrauterine pregnancy occurs while a levonorgestrel IUD is in place, it should be removed, which may result in pregnancy loss. The patient should be informed of the possibility of intrauterine fetal death or miscarriage. If the patient refuses to have the IUD removed, or if it can not be removed, the patient should be closely monitored and advised to report fever/chills, vaginal discharge or fluid leakage immediately; the risks for miscarriage, premature labor/delivery, and sepsis are increased if the IUD is left in place. Congenital anomalies in live births have occurred infrequently. No clear trend towards disorders of any kind has been observed. Because of the intrauterine administration of levonorgestrel and local exposure of the fetus to the hormone, the possibility of teratogenicity following exposure to the IUD cannot be completely excluded. Observational data support a small increased risk of masculinization of the external genitalia of females after exposure to progestins at doses greater than those currently used for oral contraception. Women using levonorgestrel IUD should be informed of isolated reports of virilization of the female fetus following local exposure to levonorgestrel during pregnancy with a levonorgestrel IUD in place.[48254] [52878] [61277] Levonorgestrel, especially an IUD, should not be used if there is a suspicion of current ectopic pregnancy. A levonorgestrel IUD is contraindicated in patients with a history of ectopic pregnancy or condition that would predispose to ectopic pregnancy. The IUD-form should not be inserted if a history of ectopic pregnancy exists, but such a history does not contraindicate oral levonorgestrel use. Health care providers should be alert to the possibility of ectopic pregnancy in women who become pregnant or complain of lower abdominal pain while on any levonorgestrel product. Up to 10% of pregnancies reported in the routine use of progestin-only oral contraceptives are ectopic; however, up to 50% of pregnancies are ectopic in women who become pregnant while an IUD is in place.[48254] [52878] [58928] [61277]

Levonorgestrel is compatible with breastfeeding. In a study of 12 lactating patients after a single 1.5 mg dose, milk levels peaked in plasma and milk 1 to 4 hours and 2 to 4 hours respectively. The amount excreted in milk after 24 hours was 0.09% of the total dose.[70365] No adverse effects due to progestin-only emergency contraceptive pills have been observed in breast-feeding infants, and experts have stated that emergency contraception with oral levonorgestrel is acceptable for breast-feeding patients.[52930] [48201] [70364] Experts consider the use of other progestin-only contraceptives such as levonorgestrel intrauterine device (IUDs) to be compatible with breast-feeding.[48201] No adverse effects on the growth or development of infants have been reported; however, there have been isolated cases of decreased milk production in women using levonorgestrel intrauterine device (IUDs).[48254] [52878] [58928] [61277] There is an increased risk of uterine perforation after IUD insertion in breast-feeding women during the early postpartum period. In a large 1-year postmarketing safety study of levonorgestrel IUD users, the incidence of uterine perforation was reported as 6.3 per 1,000 insertions for lactating women, compared to 1 per 1,000 insertions for non-lactating women.[61655] [61656] Delay IUD insertion a minimum of 6 weeks postpartum in order to minimize the risk for uterine perforation.[48201] [48254] [58928] [52878] [61277]

Levonorgestrel is absolutely contraindicated in undiagnosed abnormal vaginal bleeding or incomplete abortion. Levonorgestrel is contraindicated in patients with known or suspected cancers of reproductive organs, such as cervical cancer or uterine cancer, except as palliative therapy in selected patients. Because irregular bleeding/spotting is common during the first months of levonorgestrel IUD use, exclude endometrial pathology (polyps or cancer) prior to the insertion of levonorgestrel IUD in women with persistent or uncharacteristic bleeding.[48254] [52878] [58928] [61277]

Levonorgestrel is contraindicated in patients with known or suspected breast cancer. A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using combination oral contraceptives compared to never-users. The increased risk gradually disappears during the course of the 10 years after cessation of combination oral contraceptive use. These studies do not provide evidence for causation. The observed pattern of increased risk of breast cancer diagnosis may be due to earlier detection of breast cancer in combination oral contraceptive users, the biological effects of combination oral contraceptives, or a combination of both. Because breast cancer is rare in women less than 40 years of age, the excess number of breast cancer diagnoses in current and recent combination oral contraceptive users is small in relation to the lifetime risk of breast cancer. Breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users. Although the results were broadly similar for progestin-only oral contraceptives, the data are based on much smaller numbers of progestin-only oral contraceptive users and therefore are less conclusive than for combination oral contraceptives.

Some women may experience spotting a few days after taking a levonorgestrel emergency contraceptive. Menstrual irregularity is common among women using progestin-only postcoital and emergency contraception. If there is a delay in the onset of expected menses beyond 1 week, consider the possibility of pregnancy.[52930] With levonorgestrel intrauterine device (IUD) contraceptives, there can be alterations in menstrual bleeding patterns, including amenorrhea. Some of these changes may be expected during the early months of treatment. Patients should be instructed that menstrual irregularity may occur and to notify their prescriber of any persistent changes in bleeding patterns; these may require medical evaluation. Because the contraceptive effect of the levonorgestrel IUD is mainly due to its local effects within the uterus, ovulatory cycles with follicular rupture usually occur in women of fertile age during IUD use. Sometime atresia of the follicle is delayed and the follicle may continue to grow. Ovarian cyst formation has been reported. Most ovarian cysts are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases an ovarian cyst will disappear spontaneously during 2 to 3 months observation. Evaluate persistent ovarian cysts. Surgical intervention is not usually required.[48254] [52878] [58928] [61277]

Levonorgestrel should be used cautiously in patients with diabetes mellitus. Although the effects appear to be minimal during therapy with progestins, altered glucose tolerance secondary to decreased insulin sensitivity has been reported during hormonal contraceptive therapy.

The safety and efficacy of levonorgestrel products have only been established in females of reproductive age. Safety and efficacy of levonorgestrel is expected to be the same for postpubertal children under the age of 16 and for users 16 years of age and older. Use of levonorgestrel products in female children before menarche is not indicated.

Levonorgestrel contraceptive intrauterine devices (IUDs) and other products intended for routine contraception are contraindicated in patients with acute hepatic disease (e.g., jaundice), or hepatic tumor (benign or hepatocellular cancer).[48254] [52878] [58928] [61277] Levonorgestrel emergency contraceptive products have not been systematically studied in hepatic disease; however, guidelines recommend that emergency contraception may be used since the limited dosing poses less risk than traditional routine contraception.[52930] [55077] [48201] [70437]

No formal studies have evaluated the effect of race on the efficacy of oral levonorgestrel emergency contraceptive regimens. Asian patients, specifically Chinese women, have demonstrated a higher pregnancy rate in clinical trials with Plan B, Plan B One-Step, and Yuzpe emergency contraceptive regimens. The reason for the apparent increase in pregnancy rates is not known.

It is recommended that insertion of the levonorgestrel intrauterine device (IUD) system, be delayed until at least 6 weeks after obstetric delivery until uterine involution is complete to decrease the risk of uterine or cervical perforation. If uterine involution is delayed, consider waiting until 12 weeks postpartum before inserting the IUD. Inserting the IUD immediately after first trimester abortion is not known to increase the risk of perforation, but insertion after second trimester abortion should be delayed until uterine involution is complete.[48201] [48254] [52878] [58928] [61277]

The insertion of an intrauterine device (IUD) requires an experienced clinician who is trained in IUD insertion using aseptic technique. Health care professionals should be thoroughly familiar with insertion procedures, the specific product educational materials, product insertion instructions, prescribing information, and patient labeling before inserting the IUD.[48201] The insertion of an IUD is a simple office procedure that really only takes a couple of minutes; very effective birth control can last for up to 8 years for Mirena, 5 years for Kyleena, 3 years for Skyla, and 8 years for Liletta. Mirena is recommended for use in patients who have had at least 1 child (i.e., not nulliparous) and who is in a mutually monogamous relationship.[48254] Skyla, Liletta, and Kyleena can be used whether the patient has previously had a child or not.[52878] [58928] [61277] Insertion of a levonorgestrel IUD is contraindicated in patients with a congenital or acquired uterine anomaly, including uterine leiomyomata (fibroids), if such conditions distort the uterine cavity. Sonography may be indicated in some patients to ensure appropriate anatomical conditions for IUD placement.[48254] [52878] [58928] [61277]

The insertion of a levonorgestrel intrauterine device (IUD) is contraindicated in patients with acute pelvic inflammatory disease (PID) infection or a history of PID unless there has been a subsequent intrauterine pregnancy. IUDs increase the risk for PID. Both PID and endometritis are often associated with a sexually transmitted disease (STD), and the levonorgestrel IUDs do not protect against STDs. The risk of PID or endometritis is greater for women who have multiple sexual partners, and also for women whose sexual partner(s) have multiple sexual partners (women who are not in monogamous relationships). Women who have had PID or endometritis are at increased risk for a recurrence or re-infection. In particular, ascertain whether the woman is at increased risk of infection (e.g., leukemia, acquired immunodeficiency syndrome (AIDS) , or intravenous substance abuse). The IUDs are also contraindicated in patients with a history of postpartum endometritis or infected abortion in the past 3 months, untreated acute cervicitis or vaginitis (including bacterial vaginosis), known chlamydial or gonococcal cervical infection, genital actinomycosis, or other lower genital tract infections until the infection is controlled. The levonorgestrel IUD is contraindicated in patients with conditions associated with an increased risk for pelvic infections. The highest risk of PID occurs shortly after insertion (usually within the first 20 days), but PID may present at any time. Endometritis is more common in the first 40 days after insertion. Counsel women who receive the IUD to notify a healthcare provider if they have complaints of lower abdominal or pelvic pain, odorous vaginal discharge, unexplained bleeding, fever, or genital lesions or sores. The IUD should be removed if a patient has a pelvic infection or endometritis.[48254] [52878] [58928] [61277]

Like all hormonal contraceptives, levonorgestrel contraceptive intrauterine device (IUD) or emergency oral contraceptive use does not protect against the transmission of human immunodeficiency virus (HIV) infection or other sexually transmitted disease (STD).[52930] For patients using a levonorgestrel IUD, if the patient's relationship should cease to be mutually monogamous, or should she or her partner become HIV positive or acquire a sexually transmitted disease, the patient should be instructed to report this change to her clinician immediately; the removal of the IUD may be recommended. IUD use is contraindicated in patients with active untreated sexually transmitted disease (STD) such as acute cervicitis or vaginitis (including bacterial vaginosis), known chlamydial or gonococcal cervical infection, genital actinomycosis, or other lower genital tract infections until the infection is controlled. The use of a barrier method as a partial protection against acquiring sexually transmitted diseases should be strongly recommended. Removal of the IUD should be considered.[48254] [52878] [58928] [61277]

Syncope, bradycardia, or other neurovascular episodes may occur during insertion or removal of the levonorgestrel intrauterine device (IUD), especially in patients predisposed to these conditions or those with cervical stenosis. If decreased pulse, diaphoresis, or pallor is observed, the patient should remain supine until these signs have disappeared.[48254] [52878] [58928] [61277] Patients with a seizure disorder or epilepsy may also experience seizures during insertion. Consider administering analgesics prior to insertion.[48254]

The effect of obesity on emergency contraceptive efficacy has been assessed in clinical studies, rather than pharmacokinetic analyses alone. Pregnancy rates with use of levonorgestrel 1.5 mg as a single dose for emergency contraception were low at less than 3% across different weight and BMI categories. Pooled analyses of 4 large studies, many conducted by the World Health Organization (WHO) have showed an increase in pregnancy rates among obese women with a body mass index (BMI) more than 30 kg/m² compared to women with normal BMI levels, but the data were influenced by pregnancies reported from one study site in Nigeria.[27235] [56551] [61312] [61313] The four studies were not originally intended to be stratified in the randomization according to weight or BMI of patients.[61313] Results of the meta-analyses indicate that levonorgestrel emergency contraceptive products should still be promoted to women who need them, and not be restricted in any weight or BMI category, with additional attention for counseling and advice for obese women.[61313] The most important factor affecting how well emergency contraception works is how quickly it is taken after unprotected sex.[52930] [61315] The FDA has completed a review of available scientific data concerning the effectiveness of levonorgestrel emergency contraceptives in women who weigh more than 165 pounds (75 kg) or have a body mass index (BMI) above 25 kg/m^2. The data are conflicting and too limited to reach a definitive conclusion as to whether effectiveness is reduced in this group. The FDA continues to state that all women, regardless of BMI, can use levonorgestrel emergency contraceptive products to prevent unintended pregnancy following unprotected sexual intercourse or contraceptive failure; no changes have been made to the levonorgestrel emergency contraceptive labeling with regard to weight. Continued research is needed to determine if a high BMI provides a risk factor for emergency contraceptive failure.[61315]

Because of the potential for uterine injury from the levonorgestrel intrauterine devices (IUDs), insert and use the IUDs with caution in patients on anticoagulant therapy or with a coagulopathy. Consider removal of the IUD should these conditions arise during use.[48254] [52878] [58928] [61277]

Levonorgestrel intrauterine device (IUD) is recommended to be used cautiously and with careful consideration in patients with active thromboembolic disease or a history of thrombophlebitis or thromboembolic disease.[48254] [52878] [58928] [61277] Although thromboembolic disease is believed to be an estrogen-related effect, studies have shown that patients receiving hormonal combined contraceptives or hormonal replacement therapy (HRT) regimens containing progestins may have a higher risk of venous thromboembolic (VTE) disease. Because of the higher risk of thromboembolic disease in tobacco smoking women, patients should be advised not to smoke, particularly if they are over 35 years of age. Despite the caution against use in patients with known thrombotic disease, progestin-only contraceptives are generally the hormonal contraceptives of choice in patients with a potential risk for thrombosis when reliable contraception must be ensured and the risks of hormonal therapy are acceptable; advantages of these methods usually outweigh proven or theoretical risks. When multiple thrombosis risk factors exist, the risk of thromboembolic disease may increase; determine risk vs. benefit for use of the progestin-only contraceptive. The increase in the risk of thrombosis from newer progestin-only contraceptives (e.g., levonorgestrel IUD) is still substantially less than with combined oral contraceptives containing both estrogen and progestin. For women who are at an increased risk of thromboembolism and have multiple-risk factors for thrombosis (e.g., tobacco smoking woman age 35 and older, diabetes, hypercoagulopathy, severe hypertension, etc.), consider an IUD or other estrogen-free contraceptive if appropriate.[48201] During use of the levonorgestrel IUD in patients without a history of thrombosis, the provider should be alert to the earliest manifestations of thrombotic disorder (thrombophlebitis, cerebrovascular disease, cardiac disease, myocardial infarction, pulmonary embolism, severe hypertension, stroke, valvular heart disease, and retinal thrombosis). Should any of these thrombotic-type events occur or be suspected, or if new risk factors warrant, consider removal of the levonorgestrel IUD.[48254] [52878] [58928] [61277] Patients using oral levonorgestrel for emergency contraception would be expected to experience less of a clinical impact on the risk of thromboembolic complications due to shorter duration of use; advantages of the emergency contraceptive usually outweigh the theoretical risk; no specific precautions apply to emergency contraceptive use in patients with thromboembolic disease risk factors.[48201] [52930] [55077]

Use levonorgestrel intrauterine devices (IUDs) with caution in a patient with a history of migraine. During IUD use, a migraine that is accompanied by focal neurological symptoms (e.g., aura); the exacerbation of migraine, or the development of headache with a new pattern which is recurrent, persistent or severe requires evaluation of the cause. Sudden onset of severe headache or a sever migraine, focal migraine with asymmetrical visual loss or other symptoms may indicate transient cerebral ischemia or stroke and should prompt the consideration for removal of the IUD.[48254] Consistent with potential thrombotic effects, any change in vision or visual acuity should be examined by an ophthalmologist. Patients developing any unexplained visual disturbance require evaluation. If retinal vascular occlusion occurs, consider removal of the IUD.[48254] [52878] [58928] [61277]

No studies have been performed with any levonorgestrel contraceptive intrauterine device (IUD) or emergency contraceptive to determine the effect of renal disease or renal impairment on the disposition of the drug in these products.[52930] [48254] [52878] [58928] [61277]

Should a patient with an intrauterine device (IUD) need to have an examination that involves magnetic resonance imaging (MRI), the patient should inform her healthcare provider and scan technician that a levonorgestrel IUD is in place prior to the procedure. Some of the IUDs are MRI conditional, meaning, that the IUD can be safely scanned only under specific conditions. Refer to the specific information for the particular IUD used prior to scheduling a MRI procedure.[48254] [52878] [58928] [61277]