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 the endometrium (which reduce the likelihood of implantation).
No specific investigation of the absolute bioavailability of LYBREL in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 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 between 38% and 48%.
A summary of the single dose and multiple dose levonorgestrel and ethinyl estradiol pharmacokinetic parameters for 18 women under fasting conditions is provided in Table 1. The plasma concentrations of levonorgestrel and ethinyl estradiol reached steady-state by approximately day 14. Levonorgestrel and ethinyl estradiol concentrations did not increase from days 14 to 28, but did increase from days 1 to 28.
Table 1: Mean (SD) Pharmacokinetic Parameters of LYBREL Over a 28-Day Dosing Period
| Cmax |
| Tmax |
| t1/2 |
| AUC0-24 |
|1 ||2.4 (0.9) ||1.2 (0.4) ||- ||16 (8) |
|14 ||5.4 (2.1) ||1.7 (1.4) ||- ||68 (36) |
|28 ||5.7 (2.1) ||1.3 (0.8) ||36 (19) ||74 (41) |
|Day ||(pg/mL) ||(h) ||(h) ||(pg•h/mL) |
|1 ||47.7 (20.1) ||1.3 (0.5) ||- ||378 (140) |
|14 ||72.7 (37.2) ||1.4 (0.5) ||- ||695 (361) |
|28 ||74.4 (29.7) ||1.4 (0.5) ||21 (7) ||717 (351) |
The mean plasma concentrations of levonorgestrel and ethinyl estradiol following single (day 1) and multiple (days 14 and 28) oral administrations of levonorgestrel 90 mcg in combination with ethinyl estradiol 20 mcg to 18 healthy women is provided in Figure 1.
Figure 1: Mean Plasma ± SD† Concentrations of Levonorgestrel and Ethinyl Estradiol Following Single (Day 1) and Multiple (Days 14 and 28) Oral Administrations of Levonorgestrel 90 mcg in Combination with Ethinyl Estradiol 20 mcg to Healthy Women
The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of LYBREL has not been evaluated.
Levonorgestrel in serum is primarily bound to sex hormone-binding globulin (SHBG). Ethinyl estradiol is about 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.
Levonorgestrel: The most important metabolic pathways are reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most of the circulating metabolites are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17β-sulfate. 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.
Ethinyl estradiol: Cytochrome P450 enzymes (CYP3A4) in the liver are responsible for the 2‑hydroxylation that is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation, sulfation, and glucuronidation prior to urinary and fecal excretion. Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation.
The terminal elimination half-life for levonorgestrel in LYBREL is about 36 hours. Levonorgestrel and its metabolites are excreted in the urine (40% to 68%) and in feces (16% to 48%). The terminal elimination half-life of ethinyl estradiol in LYBREL is about 21 hours.
Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic recirculation.
No formal studies on the effect of race on the pharmacokinetic parameters of LYBREL were conducted.
No formal studies have evaluated the effect of hepatic disease on the disposition of LYBREL. However, steroid hormones may be poorly metabolized in patients with impaired liver function.
No formal studies have evaluated the effect of renal disease on the disposition of LYBREL.
See PRECAUTIONS section - Drug Interactions.