"Today, the U.S. Food and Drug Administration announced it has approved the use of Plan B One-Step (levonorgestrel) as a nonprescription product for all women of child-bearing potential. This action complies with the April 5, 2013 order of the Uni"...
Mode of action
Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and changes in the endometrium (which reduce the likelihood of implantation).
No specific investigation of the absolute bioavailability of Seasonale® (levonorgestrel, ethinyl estradiol) in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is approximately 43%.
Table 1: Mean ±SD Pharmacokinetic Parameters Following A
Single Dose Administration of Two Tablets of Seasonale® (levonorgestrel, ethinyl estradiol) in Healthy Female
Subjects Under Fasting Conditions
(mean ± SD)
(mean ± SD)
(mean ± SD)
(mean ± SD)
|Levonorgestrel||60.8 ± 25.6 ng*hr/mL||5.6 ± 1.5 ng/mL||1.4 ± 0.3 hours||29.8 ± 8.3 hours|
|Ethinyl estradiol||1307 ± 361 pg*hr/mL||145 ± 45 pg/mL||1.6 ± 0.5 hours||15.4 ± 3.2 hours|
The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Seasonale® (levonorgestrel, ethinyl estradiol) has not been evaluated.
The apparent volume of distribution of levonorgestrel and ethinyl estradiol are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5 - 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Ethinyl estradiol is about 95 - 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of combination levonorgestrel/ethinyl estradiol oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose kinetics, due in part, to increased SHBG levels that are induced by ethinyl estradiol, and a possible reduction in hepatic metabolic capacity.
Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.
First-pass metabolism of ethinyl estradiol involves formation of ethinyl estradiol-3-sulfate in the gut wall , followed by 2-hydroxylation of a portion of the remaining untransformed ethinyl estradiol by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol hydroxylation. Hydroxylation at the 4-, 6-, and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.
About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of Seasonale® (levonorgestrel, ethinyl estradiol) was about 30 hours.
Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of ethinyl estradiol after a single dose of Seasonale® (levonorgestrel, ethinyl estradiol) was found to be about 15 hours.
No formal studies on the effect of race on the pharmacokinetics of Seasonale® (levonorgestrel, ethinyl estradiol) were conducted.
No formal studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Seasonale® (levonorgestrel, ethinyl estradiol) . However, steroid hormones may be poorly metabolized in patients with impaired liver function.
No formal studies have been conducted to evaluate the effect of renal disease on the pharmacokinetics of Seasonale® (levonorgestrel, ethinyl estradiol) .
See PRECAUTIONS section – DRUG INTERACTIONS.
Last reviewed on RxList: 11/18/2008
This monograph has been modified to include the generic and brand name in many instances.
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