Description: Levonorgestrel is a synthetic progestin. It is used for contraception as an intrauterine device (IUD) or subdermal skin implant, or as an post-coital emergency oral contraceptive. The Norplant� subdermal implant consists of six, 36 mg capsules of slow-release levonorgestrel in silastic; contraception lasts for 5 years and is reversible upon capsule removal.[530] Norplant� was FDA-approved in December 1990. In 1996, the Population Research Institute petitioned the FDA to remove Norplant� from marketing, citing a high number of reported ADRs, but the product remains on the market. Norplant II�, a revised implant containing two rods and providing 3 years of contraception, was redesigned after an initial 1996 approval; a new NDA was filed in 1998 but the product remains unmarketed. Plan B�, a levonorgestrel-only emergency oral contraceptive, was FDA-approved in July 1999; the regimen is very effective at preventing pregnancy when ingested within 72 hours of unprotected sex. The regimen causes less post-dose nausea than oral combination estrogen-progestin postcoital (Yutzpe) regimens. The Mirena� IUD, releases a low amount of levonorgestrel continuously over a 5-year period; FDA approval was granted in December 2000. Mechanism of Action: The primary contraceptive effect of progestins involves the suppression of the midcycle surge of LH. The exact mechanism of action, however, is unknown. At the cellular level, progestins diffuse freely into target cells and bind to the progesterone receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH surge, thereby preventing follicular maturation and ovulation. Overall, progestin-only contraceptives prevent ovulation in 70�80% of cycles, however, the clinical effectiveness ranges 96�98%. This suggests that additional mechanisms may be involved. Other actions of progestins include alterations in the endometrium that can impair implantation and an increase in cervical mucus viscosity which inhibits sperm migration into the uterus. Following removal of Norplant� capsules, fertility rates rapidly return to normal. �Emergency oral contraception: The mechanism for postcoital oral contraception is not well understood. Evidence exists at several stages of the reproductive cycle. Most of the scientific evidence suggests that inhibition or delay of ovulation is the primary mechanism of action. However, fertilization, embryo transport, or implantation may be disrupted as secondary mechanisms. Postcoital regimens will not interupt an established (implanted) pregnancy. It is important to note that postcoital contraception is not intended to replace regular use of contraceptives. Long term effects of frequent, repetitive use of emergency contraceptive regimens are unknown. �Intrauterine contraception: The levonorgestrel IUD has mainly local progestogenic effects in the uterine cavity. Morphological changes of the endometrium are observed, including stromal pseudodecidualization, glandular atrophy, leucocytic infiltration, and a decrease in glandular and stromal mitoses. Ovulation is inhibited in some women. In a 1-year study approximately 45% of menstrual cycles were ovulatory and in another study, 75% of cycles were ovulatory after 4 years of use. The local mechanism by which levonorgestrel enhances the contraceptive activity of an IUD device is not conclusive. Several mechanisms are suggested: thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, and alteration of the endometrium. Once the IUD is removed, fertility returns rapidly. Approximately 80% of women who want to become pregnant will become pregnant in the first year after the IUD is removed. Pharmacokinetics: Levonorgestrel is administered orally for post-coital emergency contraception, orally in combination with estrogens for routine contraception (see combination products), or sub-dermally in an implantable capsule containing device for routine contraception. �Levonorgestrel oral tablets: The literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration, with bioavailability approaching 100%. Levonorgestrel is not subject to first-pass hepatic metabolism. Levonorgestrel is highly protein-bound to sex hormone-binding globulin (SHBG), albumin, and alpha1-glycoprotein. The elimination half-life following a single oral dose of 0.75 mg levonorgestrel is roughly 17�24 hours. Levonorgestrel undergoes hydroxylation and then conjugation to sulfate and glucuronide salts. No entero-hepatic recycling occurs. Levonorgestrel and its metabolites are excreted primarily in the urine; small amounts are found in the feces. �Mirena� intrauterine device (IUD): Following IUD insertion, the initial release of levonorgestrel into the uterine cavity is 20 �g/day. A stable plasma level of levonorgestrel of 150�200 pg/mL occurs after the first few weeks following insertion, indicating low systemic absorption. The mean endometrial tissue concentrations achieved with levonorgestrel IUDs are roughly 808 ng/g wet tissue weight, much higher than the endometrial tissue levels following oral levonorgestrel (i.e., roughly 3.5 ng/g). Levonorgestrel is extensively metabolized to inactive metabolites. The plasma elimination half-life of levonorgestrel is roughly 17 hours; both the parent drug and its metabolites are primarily excreted in the urine. Pharmacokinetic studies of the IUD have not been conducted in special populations (pediatric, renal insufficiency, hepatic insufficiency, and different ethnic groups). �Norplant� depot sub-dermal silastic capsules: After subdermal implantation of Norplant� capsules, levonorgestrel is essentially 100% bioavailable. Plasma concentrations average 0.3 ng/mL over 5 years but vary greatly depending on body weight and metabolism. The dose provided is about 85 �g/day initially, which drops to about 50 �g/day at 9 months and 35 �g/day at 18 months. Pharmacokinetic data for the Norplant�-II product is still unavailable. Levonorgestrel is highly protein-bound to sex hormone-binding globulin (SHBG), albumin, and alpha1-glycoprotein. Levonorgestrel is hepatically metabolized and excreted in the urine with an elimination half-life in the range of 11�45 hours.

ndications...Dosage For routine contraception: Subdermal dosage (Norplant� only): Adult females: Implant the system, containing 6 Silastic capsules (36 mg/capsule) beneath the skin of the upper arm as per system instructions during the first 7 days of the menstrual cycle. The total implanted dose is 216 mg. Remove implants within 5 years. Intrauterine dosage (Mirena� IUD only): Adult females: Insert one IUD into the uterus as per device instructions. IUD delivers 20 �g/day of levonorgestrel. Provides efficacy for up to 5 years, then remove and replace. Never reinsert a removed system. Wait until 6-weeks post-partum until insertion. For use as postcoital contraception within 72 hours of unprotected intercourse, or known or suspected contraceptive failure, in females who have no known contraindications to oral contraceptives, have achieved menarche, and are not known or suspected to be pregnant: Oral dosage (Plan B� tablets - FDA-approved regimen): Adult and adolescent females: Confirm negative pregnancy test, give 1 tablet (750 �g levonorgestrel) PO as a first dose as soon as possible after intercourse (i.e., preferably within 12�24 hours and no later than 72 hours after the event). MUST give a second dose 12 hours after the initial dose. If patient vomits within 1 hour of the initial (1st) dose, repeat the dose. An anti-emetic may be needed for some patients. Maximum Dosage Limits: Not available. Dependent on route of administration. Patients with hepatic impairment: Avoid use if significant hepatic disease is present. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Administration Oral Administration �Instruct patient on risks and warnings associated with hormonal contraceptives (see Patient Information). �NOTE: If oral contraceptives are used for emergency contraception, they must be administered as soon as possible within the 72 hours following unprotected intercourse. Subdermal Implant Administration (Norplant�) �Levonorgestrel implants should only be administered by physicians specifically trained in administering levonorgestrel by this route. �Instruct patient on risks and warnings associated with hormonal contraceptives (see Patient Information). �Norplant� is administered subdermally as 6 Silastic capsules, each containing 36 mg of levonorgestrel, which are inserted in a superficial plane beneath the skin of the upper arm during the first 7 days of the menstrual cycle. Distribution is in a fanlike pattern covering an angle of 75 degrees, each capsule 15 degrees apart at the tip. The capsules must be removed within 5 years, but may be replaced with fresh capsules, if required. Intrauterine device (IUD) Administration (Mirena�) �Levonorgestrel IUD is for insertion into the uterus and should only be administered by physicians specifically trained in administering levonorgestrel by this route. �The IUD system can be inserted at any time during the menstrual cycle. The preferred insertion time is within 7 days of the onset of a menstrual period to reduce the risk of insertion when there is an undiagnosed pregnancy. Alternatively, may be inserted immediately following a first-trimester abortion. �The retrieval threads should be visible after insertion. �Placement can be checked with ultrasound. �Removal by applying gentle traction on the threads with forceps. The arms of the system will fold upward as it is withdrawn from the uterus. The IUD should not remain in the uterus after 5 years. Never reinsert a removed system. �You may insert a new IUD immediately following removal.

Contraindications For all formulations of levonorgestrel: Available data suggest that a rapid return of fertility and normal ovulation occurs following discontinuation of levonorgestrel containing contraceptives. Levonorgestrel is classified in FDA pregnancy category X and is contraindicated for use during pregnancy or suspected pregnancy. The majority of recent studies do not indicate a teratogenic effect of progestin-only contraceptives when taken inadvertently during early pregnancy; however, the progestin should be discontinued as soon as pregnancy is suspected or detected. Levonorgestrel, especially the Mirena� IUD, should not be used if there is a suspicion of current ectopic pregnancy. The IUD-form should not be inserted if a history of ectopic pregnancy exists, but such a history does not contraindicate oral or implantable 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 levonorgestrel. Up to 10% of pregnancies reported in the routine use of progestin-only contraceptives are ectopic. Small amounts of levonorgestrel are excreted into breast-milk during routine contraceptive use, resulting in infant plasma levels that are 1�6% of those found in maternal plasma. However, no adverse effects due to progestin-only contraceptive pills have been observed in breast-feeding infants. No adverse effects on lactation production or the growth or development of infants have been reported. The American Academy of Pediatrics generally considers the use of levonorgestrel to be compatible with breast-feeding. Levonorgestrel is absolutely contraindicated in undiagnosed abnormal vaginal bleeding or incomplete abortion. Levonorgestrel implants are contraindicated in patients with known or suspected breast cancer or cancers of reproductive organs, such as cervical cancer, uterine cancer, or vaginal cancer, except as palliative therapy in selected patients. Levonorgestrel contraceptives should be avoided in patients with significant hepatic disease, jaundice or hepatic tumors (benign or hepatocellular cancer). With levonorgestrel 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 persistant changes in bleeding patterns; these may require medical evaluation. Like all hormonal contraceptives, levonorgestrel use does not protect against the transmission of human immunodeficiency virus (HIV) infection or other sexually transmitted diseases. 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. For oral emergency contraception, Plan-B�: Levonorgestrel tablets for emergency contraception are not intended to be used as a routine contraceptive. It is unknown if all precautions that apply with the use of other progestin-only oral contraceptives for routine contraception also apply to the intermittent use of levonorgestrel emergency contraception. In addition to the other listed contraindications for levonorgestrel in general, levonorgestrel should not be used in patients hypersensitive to any component of the oral product. Plan B� is not effective for the termination of 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. A pregnancy test may be needed. No formal studies have evaluated the effect of race on the efficacy of oral emergency contraceptive regimens. Chinese women have been observed in clinical trials, however, to demonstrate a higher pregnancy rate with both Plan B� and Yuzpe emergency contraceptive regimens. The reason for the apparent increase in pregnancy rates is not known. For the Mirena� IUD system: Contraindicated in anyone hypersensitive to the IUD components, including the drug, silicone and polyethylene. Health care professionals should be thoroughly familiar with insertion procedures before inserting the Mirena� IUD. The insertion of the IUD is a simple office procedure that really only takes a couple of minutes; very effective birth control can last for up to 5 years. The levonorgestrel IUD is recommended for women who have had at least one child (i.e., not nulliparous), are in a stable, mutually monogamous relationship, and have no history of ectopic pregnancy or condition that would predispose to ectopic pregnancy. Should an intrauterine pregnancy occur while the Mirena� IUD is in place, the prescriber should refer to the specific IUD literature that states considerations during such events. The Mirena� IUD should not be inserted in patients with a congenital or acquired uterine anomoly, including uterine leiomyomata (fibroids) if such conditions distort the uterine cavity. Do not insert the Mirena� IUD in patients with postpartum endometritis, infected abortion in the past 3 months, untreated acute cervicitis or untreated acute vaginitis, including bacterial vaginosis (BV) or other pelvic infections until the infection is controlled. Do not insert the IUD in patients with genital actinomycosis. Do not insert the Mirena� IUD in patients with conditions that increase the patients susceptibility to infection. Such conditions include leukemia, acquired immunodeficiency syndrome (AIDS), intravenous substance abuse, some patients on chronic corticosteroid therapy, patients with multiple sexual partners, and others. This list may not be inclusive of all conditions that might increase a patient's risk of infection. Use of IUDs has been associated with an increased risk of pelvic inflammatory disease (PID); the Mirena� IUD is not the best choice of contraception for those with a previous history of PID. The highest risk of PID occurs shortly after insertion (usually within the first 20 days). Patients with certain types of valvular heart disease or congenital heart disease and surgical systemic-pulmonary shunts are at increased risk of infective endocarditis and the IUD may represent a potential source of septic emboli. Patients at increased risk for endocarditis may need appropriate antimicrobial prophylaxis on device insertion and removal. Syncope, bradycardia or other neurovascular episodes may occur during insertion or removal of the Mirena� IUD, especially in patients predisposed to these conditions or those with cervical stenosis. If decreased pulse, diaphoresis, or pallor are observed, the patient should remain supine until these signs have disappeared. Because of the potential for uterine injury from the IUD device, use the Mirena� IUD with caution in patients on anticoagulant therapy or with coagulopathy. For the Norplant� implant system: Levonorgestrel implants should be used cautiously in patients with hyperlipidemia. Although hyperlipidemia is associated with estrogen-progestin combinations, the effects of progestin-only oral contraceptives on serum lipids have not been studied. Serum lipoproteins (HDL and LDL) should be monitored during therapy with levonorgestrel. Levonorgestrel implants should be used cautiously in patients with a history of thrombophlebitis or thromboembolic disease. Although thromboembolic disease is believed to be an estrogen-related effect, some studies have shown that patients receiving hormonal contraceptives or hormonal replacement therapy regimens containing progestins may have a higher risk of venous thromboembolic (VTE) disease. In addition, because of the higher risk of thromboembolic disease in tobacco smoking women, women should be advised not to smoke, particularly if they are over the age of 35 years. Hormonal contraceptives should also be used cautiously in patients with history of coronary artery disease, progestin intolerance, or cerebrovascular disease. Levonorgestrel implant therapy should be discontinued if any unexplained visual disturbance occurs. Hormonal contraceptives have been associated with retinal thrombosis. Although this effect is generally believed to be related to estrogen, patients should be monitored carefully for the development of ocular lesions. Levonorgestrel implants should be prescribed cautiously in patients with congestive heart failure, nephrotic syndrome or other renal disease, or cardiac disease. Hormonal contraceptives can cause fluid retention and may exacerbate any of the above conditions. Levonorgestrel implants should be used cautiously in patients with a history of major depression, migraine, or seizure disorder. Progestins may exacerbate these conditions in some patients. Some cases of seizures following administration of progestins have been reported.

Interactions Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives, including levonorgestrel implants. Pregnancy has been reported during levonorgestrel therapy in patients receiving barbiturates (e.g., phenobarbital), carbamazepine, phenytoin, primidone, or rifampin concurrently. Fosphenytoin, other rifamycins (e.g., rifabutin and rifapentine), modafinil, oxcarbazepine, pioglitazone, ritonavir, topiramate, and troglitazone also induce hepatic enzymes in this manner. An alternate or additional form of contraception should be considered in patients prescribed levonorgestrel who require concomitant therapy with enzyme-inducing anticonvulsants, rifamycins, modafinil, or troglitazone. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. St. John's wort, Hypericum perforatum appears to interact with estrogens and oral contraceptives. One report noted intermenstrual bleeding after the concurrent use of St. John's wort in 8 premenstrual women who had been on oral contraceptives for long durations of time. Intermenstrual bleeding implies that there may be a loss of contraceptive or hormonal-replacement efficacy. It is thought that St. John's wort induces hormone metabolism via induction of the hepatic CYP3A4 isoenzyme. The interaction occurred within 1 week of beginning St. John's wort in five of the cases. In 3 patients for whom follow-up was available, the discontinuation of St. John's wort resolved the bleeding abnormalities.[2717] It is possible that, as with other CYP3A4 inducers, St. John's wort could also reduce the therapeutic efficacy of progestin-only contraceptives (e.g., levonorgestrel, medroxyprogesterone, and norgestrel). Women should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of these combinations is recommended. Oral levonorgestrel-containing emergency contraceptive regimens may interact with warfarin and concurrent use may require patient education and monitoring. A case report of an interaction of warfarin with a levonorgestrel-only oral emergency contraceptive regimen has been described. The patient involved had familial antithrombin deficiency and was stabilized on warfarin as her only medication. The INR increased to 8.1 (without bleeding complications) from 2.1 within 3 days after receiving levonorgestrel. With corrective action, the warfarin was resumed at the usual dose without complication 2 days later. The report speculated that levonorgestrel displaced warfarin from plasma protein binding sites; however, inhibition of hepatic CYP2C9 by levonorgestrel may have decreased the metabolism of warfarin. This is the only report of this type of interaction available.[3014]

Adverse Reactions For acute oral emergency contraception, Plan-B�: Adverse reactions associated with levonorgestrel used orally as an oral contraceptive are usually minimal. Nausea/vomiting occurs in roughly 23%/5.6% of patients respectively versus 51%/19% of those who take estrogen-progestin oral emergency contraceptives (e.g., the Yuzpe methods). Other common side effects include abdominal pain (18%), fatigue (17%), headache (17%), menstrual changes [heavier (13%) or lighter bleeding (13%)], dizziness (11%) and breast tenderness (11%). A pregnancy test is indicated if menstrual bleeding does not occur within 21 days of taking the emergency regimen. Serious side effects are not common. For the Norplant� implant system and routine systemic use of levonorgestrel in general: Adverse reactions that have been reported frequently, particularly during the early months of implantable levonorgestrel therapy, include breakthrough bleeding, spotting, menstrual irregularity, scanty bleeding, and amenorrhea. Other reported adverse reactions during levonorgestrel therapy include abdominal pain; acne vulgaris or exfoliative dermatitis (e.g., eczema); anorexia; breast discharge; cervicitis; dizziness; hirsutism; leukorrhea; nausea/vomiting; anorexia, vaginitis; and appetite stimulation or weight gain. As with all hormonal contraceptives, headache patterns may change during levonorgestrel use. Consider removal if migraine headaches or exceptionally severe headaches occur, especially if migraine is focal in nature with assymmetrical visual impairment or other symptoms that suggest transient cerebral ischemia. Levonorgestrel implants can cause a type of injection site reaction. Pain or pruritus at the implant site have been reported in 5�6% of patients. In addition, there is growing concern regarding the removal of the six silicone rods that release levonorgestrel. Removal of the implants can require surgery and may be painful or result in scarring. Fluid retention and/or edema may occur in patients receiving levonorgestrel. Patients with heart failure and/or renal disease may experience an exacerbation of their condition. Patients receiving levonorgestrel or other hormonal contraceptives can experience emotional lability. This adverse effect may be manifest as mental depression, anxiety or nervousness, frustration, anger, or other emotional outbursts. Thromboembolism or thrombus formation has been associated with high doses of progestins. Other rare adverse reactions that may occur during progestin therapy may include retinal thrombosis, elevated blood pressure, hepatoma, hepatitis (and elevated hepatic enzymes), biliary obstruction or cholestasis, and hyperglycemia. Marked hypertension, the appearance of jaundice, or severe arterial disease such as stroke or myocardial infarction are reasons to consider levonorgestrel discontinuation. Norplant� has been possibly associated with the development of pseudotumor cerebri (benign intracranial hypertension) in less than 1% of patients. For the Mirena� IUD system: Syncope, bradycardia or other neurovascular episodes may occur during insertion or removal of the Mirena� IUD, especially in patients predisposed to these conditions or with cervical stenosis. If decreased pulse, diaphoresis, or pallor are observed, the patient should remain supine until these signs have disappeared. Because levonorgestrel in the Mirena� IUD system is released just within the uterus, very few systemic side effects are expected to occur. The most serious adverse events include device expulsion; ectopic pregnancy (rate of 1 per 1000 users per year); pelvic inflammatory disease or other infection; sepsis (e.g., toxic shock syndrome or group A streptococcal sepsis); and risks of embedment of the device or perforation of the cervix or uterus (uterine rupture) by the IUD device. Most serious events are infrequent in nature with proper patient selection and education. Other adverse events reported in 5% of Mirena� IUD users include: abdominal pain; abnormal pap smear; acne or skin disorder not specified; back pain; depression; dysmenorrhea; headache; hypertension; mastalgia; nausea; nervousness; leukorrhea; libido decrease; sinusitis; upper respiratory infection; vaginitis; and weight gain. Other reported adverse reactions in <= 3% of patients included: failed insertion; anemia; cervicitis; dyspareunia; eczema; hair loss (alopecia); migraine; vomiting. The Mirena� IUD should be removed for any of the following medical reasons: menorrhagia and/or metrorrhagia that produces anemia; AIDS or other sexually transmitted disease; pelvic infection; endometritis; genital actinomycosis; intractable pelvic or uterine pain or severe dyspareunia; pregnancy; endometrial or cervical malignancy; or uterine or cervical perforation. Consider removal if migraine headaches or exceptionally severe headaches occur, especially if migraine is focal in nature with assymmetrical vision impairment or other symptoms that suggest transient cerebral ischemia. Marked hypertension, the appearance of jaundice, or severe arterial disease such as stroke or myocardial infarction are other reasons to consider IUD discontinuation.

Levonorgestrel Mirena�, Norplant�, Plan B� | Mirena� IUD | Plan B�

530. Polaneczky M, Slap G, Forke C et al. The use of levonorgestrel implants (Norplant) for contraception in adolescent mothers. N Engl J Med 1994;331:1201�6.

2717. Yue QY, Bergquist C, Gerden B. Seven cases of decreased effect of warfarin during concomitant treatment with St. John's wort (letter). Lancet 2000;355:575.

3014. Ellison J, Thomson AJ, Greer IA. Apparent interaction between warfarin and levonorgestrel used for emerency contraception. BMJ 2000;321:1382.