CLINICAL PHARMACOLOGY
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).
PHARMACOKINETICS
ABSORPTION
No specific investigation of the absolute bioavailability of Seasonale® 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® in Healthy Female Subjects Under Fasting Conditions
| Analyte |
AUCt (mean ± SD) |
Cmax (mean ± SD) |
Tmax (mean ± SD) |
T1/2 (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® has not been evaluated. Distribution
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.
Metabolism
Following absorption, levonorgestrel is conjugated at the 17(beta)-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3(alpha),5(beta)-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3(alpha),5(alpha)-tetrahydrolevonorgestrel and 16(beta)-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.
Excretion
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® 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® was found to be about 15 hours.
SPECIAL POPULATIONS
Race
No formal studies on the effect of race on the pharmacokinetics of Seasonale® were conducted. Hepatic Insufficiency
No formal studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Seasonale®. However, steroid hormones may be poorly metabolized in patients with impaired liver function.
Renal Insufficiency
No formal studies have been conducted to evaluate the effect of renal disease on the pharmacokinetics of Seasonale®.
DRUG-DRUG INTERACTIONS
See PRECAUTIONS section - Drug Interactions.
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