TRIVORA- levonorgestrel and ethinyl estradiol
RPK Pharmaceuticals, Inc.
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
Each Trivora cycle of 28 tablets consists of three different drug phases as follows: Phase 1 comprised of 6 blue tablets, each containing 0.050 mg of levonorgestrel (d(-)-13 beta-ethyl-17-alpha-ethinyl-17-beta-hydroxygon-4-en-3-one), a totally synthetic progestogen, and 0.030 mg of ethinyl estradiol (19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3, 17-diol); phase 2 comprised of 5 white tablets, each containing 0.075 mg levonorgestrel and 0.040 mg ethinyl estradiol; and phase 3 comprised of 10 pink tablets, each containing 0.125 mg levonorgestrel and 0.030 mg ethinyl estradiol; then followed by 7 peach inert tablets. The inactive ingredients present in the blue, white and pink tablets are lactose monohydrate, magnesium stearate, povidone and starch (corn). Each blue tablet also contains FD&C Blue #1. Each pink tablet also contains FD&C Red #40. Each inactive peach tablet contains the following inactive ingredients: anhydrous lactose, FD&C Yellow #6, lactose monohydrate, magnesium stearate and microcrystalline cellulose.
Combination oral contraceptives primarily 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).
Levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%). Levonorgestrel is not subject to first-pass metabolism or enterohepatic circulation and therefore does not undergo variations in absorption after oral administration. 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%.
There have been no formal multiple-dose studies conducted using levonorgestrel and ethinyl estradiol tablets – triphasic regimen. However, a multiple-dose study was done in 22 women using a monophasic, low dose combination of 0.10 mg levonorgestrel and 0.02 mg ethinyl estradiol. Maximum serum concentrations of levonorgestrel were found to be 2.8 ± 0.9 ng/mL (mean ± SD) at 1.6 ± 0.9 hours after a single dose, reaching a steady state at day 19. Observed levonorgestrel concentrations increased from day 1 to days 6 and 21 by 34% and 96%, respectively. Unbound levonorgestrel concentrations subsequently increased from day 1 to days 6 and 21 by 25% and 83%, respectively, however, the accumulation of unbound levonorgestrel was approximately 14% less than total levonorgestrel accumulation. The kinetics of total levonorgestrel were non-linear due to an increase in binding of levonorgestrel to SHBG, which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol. Ethinyl estradiol reached maximum serum concentrations of 62 ± 21 pg/mL at 1.5 ± 0.5 hours after a single dose, reaching steady state at day 6. Ethinyl estradiol concentrations increased by 19% from days 1 to 21 consistent with an elimination half-life of 18 hours.
Single-dose studies with levonorgestrel and ethinyl estradiol tablets – triphasic regimen have been conducted with the following data reported below in Table I. Plasma concentrations have been corrected below to reflect single tablet dosing/day.
|Dose LNG/EEµg||Cmax ng/mL||tmax h||t1/2 h||AUCng∙h/mL|
|50/30||1.7 (0.1)||1.3 (0.1)||23 (2.2)||17 (1.5)|
|75/40||2.1 (0.2)||1.5 (0.2)||15 (1.2)||21 (2.0)|
|125/30||2.5 (0.2)||1.6 (0.1)||23 (1.4)||34 (3.0)|
|Ethinyl Estradiol (EE)|
|Dose LNG/EEµg||Cmax pg/mL||tmax h||t1/2 h||AUCpg∙h/mL|
|50/30||141 (9)||1.4 (0.1)||8.1 (1.0)||1126 (113)|
|75/40||179 (13)||1.6 (0.2)||14 (1.7)||2177 (244)|
|125/30||115 (10)||1.5 (0.1)||8.8 (1.6)||1072 (170)|
Levonorgestrel is bound to SHBG and albumin. Levonorgestrel has high binding affinity for SHBG that is 60% of that of testosterone. Ethinyl estradiol is about 97% bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but will induce SHBG synthesis.
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