SRONYX

SRONYX- levonorgestrel and ethinyl estradiol
RPK Pharmaceuticals, Inc.

PHYSICIAN LABELING

Rx only

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

DESCRIPTION

Each cycle of Sronyx® (Levonorgestrel and Ethinyl Estradiol Tablets USP) consists of 21 white active tablets each containing 0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol; and seven peach tablets – inert. The inactive ingredients are Croscarmellose Sodium NF, Lactose Monohydrate NF, Magnesium Stearate NF, Microcrystalline Cellulose (PH 102) NF, and Povidone (K29/32) NF. Each inactive, placebo tablet contains the following inactive ingredients: FD & C Yellow #6 Lake 35-42%, Lactose Anhydrous (DT Micro) NF, Lactose Monohydrate (200M) NF, Magnesium Stearate NF and Microcrystalline Cellulose NF.

Levonorgestrel has a molecular weight of 312.4 and a molecular formula of C21 H28 O2 . Ethinyl estradiol has a molecular weight of 296.4 and a molecular formula of C20 H24 O2 . The structural formulas are as follows:

Chemical Structure
(click image for full-size original)

CLINICAL PHARMACOLOGY

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 levonorgestrel and ethinyl estradiol of Levonorgestrel and Ethinyl Estradiol Tablets USP in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration 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 absolute bioavailability of ethinyl estradiol is about 40%.

After a single dose of three Levonorgestrel and Ethinyl Estradiol Tablets USP to 17 women under fasting conditions, the extents of absorption of levonorgestrel and ethinyl estradiol were 98.6% and 99.0%, respectively, relative to the same dose of the 2 drugs when given as a microcrystalline suspension in water. The effect of food on the bioavailability of Levonorgestrel and Ethinyl Estradiol Tablets USP following oral administration has not been evaluated.

The pharmacokinetics of levonorgestrel and ethinyl estradiol following daily administration of Levonorgestrel and Ethinyl Estradiol Tablets USP for 21 days per cycle for three cycles, were determined in 18 women. Estimates of the pharmacokinetic parameters of levonorgestrel and ethinyl estradiol following single and multiple dose administration of Levonorgestrel and Ethinyl Estradiol Tablets USP are summarized in Table I. Mean levonorgestrel and ethinyl estradiol levels after a single dose and on day 21 at steady state are shown in Figure I.

The pharmacokinetics of total levonorgestrel are non-linear due to an increase in binding to SHBG, which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol. Increased binding of levonorgestrel to SHBG leads to decreased clearance of levonorgestrel. Observed maximum levonorgestrel concentrations increased from day 1 to day 21 of the 1st and 3rd cycles by 66% and 83%, respectively.

Figure 1
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In calculating the mean concentration for ethinyl estradiol, any individual subject value below the quantifiable limit (i.e., 20 pg/mL) was converted to 0; and the 0 values were included for calculation of the mean concentration.

Table I provides a summary of Levonorgestrel and Ethinyl Estradiol pharmacokinetic parameters.

TABLE I MEAN (SD) PHARMACOKINETIC PARAMETERS OF LEVONORGESTREL AND ETHINYL ESTRADIOL TABLETS USP AFTER SINGLE DOSE AND AFTER MULTIPLE DOSING FOR 3 CYCLES
Cmax = maximum concentrationtmax = time to maximum concentrationAUC = area under the drug concentration curve from time 0 to infinityCL/f = oral clearanceVz = volume of distributionSHBG = sex hormone-binding globulinAUC (0-24) = area under the drug concentration time curve from time 0 to 24 hours; this represents the area for one dosing interval at steady state.
Levonorgestrel
Day(cycle)Cmaxng/mLtmaxhAUCng∙h/mLCL/FmL/min/kgVzLSHBGnmol/L
12.36 (0.79)1.3 (0.4)29.2 (10.0)1.0 (0.3)129 (46)64.5 (22.0)
AUC (0-24h)ng∙h/mL
21 (1)4.04 (2.08)1.0 (0.3)43.8 (22.4)0.73 (0.34)106 (42)94.7 (37.4)
21 (3)4.53 (1.94)1.0 (0.3)49.5 (24.5)0.65 (0.33)96 (35)107.4 (45.8)
Ethinyl Estradiol
Day(cycle)Cmaxpg/mLtmaxhAUC (0-24)pg∙h/mL
149.5 (13.4)1.5 (0.4)298 (215)
21(1)66.2 (29.5)1.4 (0.4)596 (494)
21(3)58.1 (19.3)1.4 (0.3)417 (289)

Distribution

Levonorgestrel in serum is primarily bound to SHBG. Protein binding values for levonorgestrel are provided in Table II. Ethinyl estradiol is about 97% bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.

TABLE II. Protein binding (mean ± SD) of levonorgestrel in pools of serum samples collected from 18 women after a single dose of Levonorgestrel and Ethinyl Estradiol Tablets USP and following administration (once daily) over 3×21 days.
Parameter Single Dose Cycle 2 Cycle 4
% free 1.11 (0.27) 0.79 (0.22) 0.80 (0.23)
% SHBG-bound 64.5 (8.54) 75.6 (6.59) 74.7 (7.89)
% albumin-bound 34.4 (8.28) 23.6 (6.41) 24.5 (7.67)

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