Lutera

LUTERA- levonorgestrel and ethinyl estradiol
RPK Pharmaceuticals, Inc.

Rx only

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

DESCRIPTION

Each active, white tablet (21) contains 0.1 mg of levonorgestrel, d (-)-13β-ethyl-17α-ethinyl-17β- hydroxygon-4-en-3-one, a totally synthetic progestogen, and 0.02 mg of ethinyl estradiol, 17α-ethinyl- 1,3,5(10)-estratriene-3,17β-diol. The inactive ingredients present are croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone.

Each inactive, peach tablet (7) contains the following inactive ingredients: FD&C Yellow #6, lactose anhydrous, lactose monohydrate, magnesium stearate, and microcrystalline cellulose.

Chemical Structure
(click image for full-size original)
Chemical Structure
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C21 H28 O2 M.W. 312.45C20 H24 O2 M.W. 296.4

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 Lutera 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 Lutera 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 ± 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 ng/mL. Observed levonorgestrel concentrations increased from day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively (Figure I). 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
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TABLE I provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters.

TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF LUTERA OVER A 21-DAY DOSING PERIOD
Levonorgestrel
DayCm a x ng/mLTm a x hAUCng∙h/mLCL/FmL/h/kgVλz/FL/kgSHBGnmol/L
12.75 (0.88)1.6 (0.9)35.2 (12.8)53.7 (20.8)2.66 (1.09)57 (18)
64.52 (1.79)1.5 (0.7)46.0 (18.8)40.8 (14.5)2.05 (0.86)81 (25)
216.00 (2.65)1.5 (0.5)68.3 (32.5)28.4 (10.3)1.43 (0.62)93 (40)
Unbound Levonorgestrel
pg/mLhpg∙h/mLL/h/kgL/kgfu %
151.2 (12.9)1.6 (0.9)654 (201)2.79 (0.97)135.9 (41.8)1.92 (0.30)
677.9 (22.0)1.5 (0.7)794 (240)2.24 (0.59)112.4 (40.5)1.80 (0.24)
21103.6 (36.9)1.5 (0.5)1177 (452)1.57 (0.49)78.6 (29.7)1.78 (0.19)
Ethinyl Estradiol
pg/mLhpg∙h/mLmL/h/kgL/kg
162.0 (20.5)1.5 (0.5)653 (227)567 (204)14.3 (3.7)
676.7 (29.9)1.3 (0.7)604 (231)610 (196)15.5 (4.0)
2182.3 (33.2)1.4 (0.6)776 (308)486 (179)12.4 (4.1)

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