LYBREL®
(90 mcg levonorgestrel and 20 mcg ethinyl estradiol)
Tablets

Rx only

Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

DESCRIPTION
Twenty-eight (28) yellow tablets each containing 90 mcg of levonorgestrel (17α)-(–)13-ethyl-17-hydroxy-18, 19-dinorpregn-4-en-20-yn-3-one, a totally synthetic progestogen, and 20 mcg of ethinyl estradiol, (17α)-19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol. The inactive ingredients present are microcrystalline cellulose, lactose monohydrate, magnesium stearate, polacrilin potassium, hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide, polyethylene glycol 1450, montanic ester wax.

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 the endometrium (which reduce the likelihood of implantation).

Pharmacokinetics

Absorption
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  LNG
Day
Cmax
(ng/mL)
Tmax
(h)
t1/2
(h)
AUC0-24
(ng•h/mL)
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)
EE
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 eva luated.

Distribution
Levonorgestrel in serum is primarily boun