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Alesse

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Alesse

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 ALESSE (levonorgestrel and ethinyl estradiol) 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%.

After a single dose of ALESSE (levonorgestrel and ethinyl estradiol) to 22 women under fasting conditions, maximum serum concentrations of levonorgestrel are 2.8 ± 0.9 ng/mL (mean ± SD) at 1.6 ± 0.9 hours. At steady state, attained from day 19 onwards, maximum levonorgestrel concentrations of 6.0 ± 2.7 ng/mL are reached at 1.5 ± 0.5 hours after the daily dose. The minimum serum levels of levonorgestrel at steady state are 1.9 ± 1.0 ng/mL. Observed levonorgestrel concentrations increased from day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively (Figure 1). Unbound levonorgestrel concentrations increased from day 1 to days 6 and 21 by 25% and 83%, respectively. The kinetics of total levonorgestrel are non-linear due to an increase in binding of levonorgestrel to sex hormone binding globulin (SHBG), which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol.

Following a single dose, maximum serum concentrations of ethinyl estradiol of 62 ± 21 pg/mL are reached at 1.5 ± 0.5 hours. At steady state, attained from at least day 6 onwards, maximum concentrations of ethinyl estradiol were 77 ± 30 pg/mL and were reached at 1.3 ± 0.7 hours after the daily dose. The minimum serum levels of ethinyl estradiol at steady state are 10.5 ± 5.1 pg/mL. Ethinyl estradiol concentrations did not increase from days 1 to 6, but did increase by 19% from days 1 to 21 (FIGURE I).

FIGURE I : Mean (SE) levonorgestrel and ethinyl estradiol serum concentrations in 22 subjects receiving ALESSE (levonorgestrel and ethinyl estradiol) (100μg levonorgestrel and 20μg ethinyl estradiol)

Mean (SE) levonorgestrel and ethinyl estradiol serum concentrations - Illustration

TABLE I provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters.

TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF ALESSE (levonorgestrel and ethinyl estradiol) OVER A 21-DAY DOSING PERIOD

Day Levonorgestrel
Cmax
ng/mL
Tmax
h
AUC
ng•h/mL
CL/F
mL/h/kg
Vλz/
FL/kg
SHBG
nmol/L
1 2.75 (0.88) 1.6 (0.9) 35.2 (12.8) 53.7 (20.8) 2.66 (1.09) 57 (18)
6 4.52 (1.79) 1.5 (0.7) 46.0 (18.8) 40.8 (14.5) 2.05 (0.86) 81 (25)
21 6.00 (2.65) 1.5 (0.5) 68.3 (32.5) 28.4 (10.3) 1.43 (0.62) 93 (40)
  Unbound Levonorgestrel
pg/mL h pg•h/mL L/h/kg L/kg fu %
1 51.2 (12.9) 1.6 (0.9) 654 (201) 2.79 (0.97) 135.9 (41.8) 1.92 (0.30)
6 77.9 (22.0) 1.5 (0.7) 794 (240) 2.24 (0.59) 112.4 (40.5) 1.80 (0.24)
21 103.6 (36.9) 1.5 (0.5) 1177 (452) 1.57 (0.49) 78.6 (29.7) 1.78 (0.19)
  pg/mL h Ethinyl Estradiol
pg•h/mL
Estradiol
mL/h/kg
L/kg  
1 62.0 (20.5) 1.5 (0.5) 653 (227) 567 (204) 14.3 (3.7)  
6 76.7 (29.9) 1.3 (0.7) 604 (231) 610 (196) 15.5 (4.0)  
21 82.3 (33.2) 1.4 (0.6) 776 (308) 486 (179) 12.4 (4.1)

Distribution

Levonorgestrel in serum is primarily bound to SHBG. Ethinyl estradiol is about 97% bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.

Metabolism

Levonorgestrel: The most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most of the metabolites that circulate in the blood 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 and glucuronidation prior to urinary and fecal excretion. Levels of Cytochrome P450 (CYP3A) vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and undergoes enterohepatic circulation.

Excretion

The elimination half-life for levonorgestrel is approximately 36 ± 13 hours at steady state. Levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in feces. The elimination half-life of ethinyl estradiol is 18 ± 4.7 hours at steady state.

Special Populations

Race

Based on the pharmacokinetic study with ALESSE (levonorgestrel and ethinyl estradiol) , there are no apparent differences in pharmacokinetic parameters among women of different races.

Hepatic insufficiency

No formal studies have evaluated the effect of hepatic disease on the disposition of ALESSE (levonorgestrel and ethinyl estradiol) . However, steroid hormones may be poorly metabolized in patients with impaired liver function.

Renal insufficiency

No formal studies have evaluated the effect of renal disease on the disposition of ALESSE (levonorgestrel and ethinyl estradiol) .

Drug-drug interactions

See PRECAUTIONS section - DRUG INTERACTIONS

Last reviewed on RxList: 4/3/2009
This monograph has been modified to include the generic and brand name in many instances.

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