Levonorgestrel (Plan B®)
Levonorgestrel
Brand Names: Jadelle®, Mirena®, Norplant®, Plan B®
Classification:
Hormones and Hormone Modifiers
» Contraceptives
» » Progestins
Hormones and Hormone Modifiers
» Progestins
Description: Levonorgestrel is a synthetic progestin. It is used for routine contraception as an intrauterine device (IUD) or as a post-coital emergency oral contraceptive. 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. Some public and health care professional organizations have lobbied for the provision of Plan B® contraceptives as non-prescription (OTC) products. The FDA issued a ‘Not Approvable’ letter in May 2004 for the OTC use of Plan B®. Barr resubmitted the application for the OTC use of Plan B® in patients 17 years of age or older, with the product remaining prescription (Rx only) for patients 16 years of age or younger. The FDA issued an ‘Approvable’ letter in August 2005; however, they are seeking public comment on the approval of a product that is OTC for patients 17 years of age or older and Rx only for patients 16 years of age or younger. The FDA did not commit to any time period for final approval. The Mirena® IUD releases a low amount of levonorgestrel continuously over a 5-year period for routine contraception; FDA approval was granted in December 2000.
Historically, levonorgestrel was also used in an implantable contraceptive device; the Norplant® subdermal implant was FDA approved in December 1990 and consisted of six, 36 mg capsules of slow-release levonorgestrel in silastic; contraception lasted for 5 years. In 1996, the Population Research Institute petitioned the FDA to remove Norplant® from marketing, citing a high number of reported ADRs. However, the product remained in use until 2002, even though sales were halted in 2000 due to concerns that available lots might not provide enough active ingredient to support 5-years of contraception. Additional testing proved the current lots of the product were not defective. Wyeth discontinued marketing of Norplant® in 2002 as a business decision; women with current implants should have them removed on the appropriate 5-year date and will need to pursue other methods of birth control. Jadelle®, a revised implant containing two rods and providing 3 years of contraception, was FDA-approved in 1996 but the product remains unmarketed at this time; Wyeth continues to evaluate the product for potential sale.
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 interrupt 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, leukocytic 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 is administered intrauterine as a progestin-only IUD. Previously, the drug was also administered as a sub-dermal implantable device.
- 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 mcg/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: NOTE: no longer marketed in the US. 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 mcg/day initially, which drops to about 50 mcg/day at 9 months and 35 mcg/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.
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References
. 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.
[ Revised 4/11/2006 4:38:00 PM ]
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