"The U.S. Food and Drug Administration today announced that it has approved an amended application submitted by Teva Women's Health, Inc. to market Plan B One-Step (active ingredient levonorgestrel) for use without a prescription by women 15 years"...
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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 (levonorgestrel and ethinyl estradol tablets) 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 (levonorgestrel and ethinyl estradol tablets) Over
a 28-Day Dosing Period
|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)|
|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 (levonorgestrel and ethinyl estradol tablets) 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, 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 (levonorgestrel and ethinyl estradol tablets) 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 (levonorgestrel and ethinyl estradol tablets) 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 (levonorgestrel and ethinyl estradol tablets) were conducted.
No formal studies have evaluated the effect of hepatic disease on the disposition of LYBREL (levonorgestrel and ethinyl estradol tablets) . 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 (levonorgestrel and ethinyl estradol tablets) .
See PRECAUTIONS section - DRUG INTERACTIONS.
The efficacy and safety of LYBREL (levonorgestrel and ethinyl estradol tablets) were studied in 2 one-year clinical trials of subjects age 1849. There were no exclusions for body mass index (BMI), weight, or bleeding history.
The primary efficacy and safety study (313-NA) was a one-year open-label clinical trial that treated 2,134 subjects in North America. Of these subjects 1,213 (56.8%) discontinued prematurely, including 102 (4.8%) discontinued by the Sponsor for early study closure. The mean weight of subjects in this study was 70.38 kg. The efficacy of LYBREL (levonorgestrel and ethinyl estradol tablets) was assessed by the number of pregnancies that occurred after the onset of treatment and within 14 days of the last dose. Among subjects 35 years or less, there were 23 pregnancies (4 of these occurred during the interval 1 to 14 days after the last day of pill use) during 12,572 28-day pill packs of use. The resulting total Pearl Index was 2.38 (95% CI: 1.51, 3.57) and the one-year life table pregnancy rate was 2.39 (95% CI: 1.57, 3.62). Pill pack cycles during which subjects used back-up contraception or were not sexually active were not included in these calculations. Among women 35 years or less who took the pills completely as directed, there were 15 pregnancies (method failures) resulting in a Pearl Index of 1.55 (95% CI: 0.87, 2.56) and the one-year life table pregnancy rate was 1.59 (95% CI: 0.95-2.67).
In a second supportive study conducted in Europe (315-EU), 641 subjects were randomized to LYBREL (levonorgestrel and ethinyl estradol tablets) (n=323) or the cyclic comparator of 100 mcg levonorgestrel and 20 mcg ethinyl estradiol (n=318). The mean weight of subjects in this study was 63.86 kg. The efficacy analysis among women 35 years or less included 2,756 LYBREL (levonorgestrel and ethinyl estradol tablets) pill packs and 2,886 cyclic comparator pill packs. There was one pregnancy in the LYBREL (levonorgestrel and ethinyl estradol tablets) group that occurred within 14 days following the last dose. There were three pregnancies in the cyclic comparator group.
Inhibition of Menses (Bleeding Profile)
The bleeding profile for subjects in Study 313-NA also was assessed. Women with a history of unscheduled bleeding and/or spotting were not excluded from the study.
In those subjects who provided complete bleeding data, the percentage of patients who were amenorrheic in a given cycle and remained amenorrheic through cycle 13 (cumulative amenorrhea rate) was determined (Figure 2).
Figure 2: Percentage of Subjects with Cumulative Amenorrhea
for Each Pill Pack through Pill Pack 13
When prescribing LYBREL (levonorgestrel and ethinyl estradol tablets) , the convenience of having no scheduled menstrual bleeding should be weighed against the inconvenience of unscheduled bleeding and spotting (see WARNINGS).
Last reviewed on RxList: 12/5/2008
This monograph has been modified to include the generic and brand name in many instances.
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