Metabolism
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.

Excretion
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.

Special Populations

Race
No formal studies on the effect of race on the pharmacokinetic parameters of LYBREL were conducted.

Hepatic Insufficiency
No formal studies have eva luated the effect of hepatic disease on the disposition of LYBREL. However, steroid hormones may be poorly metabolized in patients with impaired liver function.

Renal Insufficiency
No formal studies have eva luated the effect of renal disease on the disposition of LYBREL.

Drug-Drug Interactions
See PRECAUTIONS section - Drug Interactions.

INDICATIONS AND USAGE
LYBREL is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

Oral contraceptives are highly effective for pregnancy prevention. Table 2 lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and implants, depend upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

Table 2: Percentage of Women Experiencing an Unintended Pregnancy During The First Year of Typical Use and The First Year of Perfect Use of Contraception and The Percentage Continuing Use at The End of the First Year. United States.    % of Women Experiencing an Unintended Pregnancy
within the First Year of Use  % of Women
Continuing Use at
One Year3
Method (1)  Typical Use1 (2) Perfect Use2 (3)  (4) 
Chance4 85  85   
Spermicides5 26  6  40 
Periodic abstinence 25    63 
   Calendar    9   
   Ovulation Method&nb