SEASONALE- levonorgestrel / ethinyl estradiol
Duramed Pharmaceuticals, Inc.
Seasonale® (levonorgestrel/ethinyl estradiol tablets) is an extended-cycle oral contraceptive consisting of 84 pink active tablets each containing 0.15 mg of levonorgestrel, a synthetic progestogen and 0.03 mg of ethinyl estradiol, and 7 white inert tablets (without hormones).
The chemical formula of levonorgestrel USP is 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-, (-)-, and the chemical formula of ethinyl estradiol USP is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-. The structural formulas are as follows:
Levonorgestrel C21 H28 O2 MW: 312.4
Ethinyl Estradiol C20 H24 O2 MW: 296.4
Each pink active tablet contains the following inactive ingredients: anhydrous lactose NF, FD&C blue no. 1, FD&C red no. 40, hydroxypropyl methylcellulose USP, microcrystalline cellulose NF, polyethylene glycol NF, magnesium stearate NF, polysorbate 80 NF, and titanium dioxide USP. Each white inert tablet contains the following inactive ingredients: anhydrous lactose NF, hydroxypropyl methylcellulose USP, microcrystalline cellulose NF, and magnesium stearate NF.
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 changes in the endometrium (which reduce the likelihood of implantation).
No specific investigation of the absolute bioavailability of Seasonale in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 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 approximately 43%.
AUCt(mean ± SD)
Cmax(mean ± SD)
Tmax(mean ± SD)
T1/2(mean ± SD)
|60.8 ± 25.6ng*hr/mL||5.6 ± 1.5 ng/mL||1.4 ± 0.3 hours||29.8 ± 8.3 hours|
|1307 ± 361pg*hr/mL||145 ± 45 pg/mL||1.6 ± 0.5 hours||15.4 ± 3.2 hours|
The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Seasonale has not been evaluated.
The apparent volume of distribution of levonorgestrel and ethinyl estradiol are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5 — 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Ethinyl estradiol is about 95 — 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of combination levonorgestrel/ethinyl estradiol oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose kinetics, due in part, to increased SHBG levels that are induced by ethinyl estradiol, and a possible reduction in hepatic metabolic capacity.
Following absorption, levonorgestrel is conjugated at the 17ß-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5ß-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16ß-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. 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.
First-pass metabolism of ethinyl estradiol involves formation of ethinyl estradiol-3-sulfate in the gut wall , followed by 2-hydroxylation of a portion of the remaining untransformed ethinyl estradiol by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol hydroxylation. Hydroxylation at the 4-, 6-, and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.
About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of Seasonale was about 30 hours.
Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of ethinyl estradiol after a single dose of Seasonale was found to be about 15 hours.
No formal studies on the effect of race on the pharmacokinetics of Seasonale were conducted.
No formal studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Seasonale . However, steroid hormones may be poorly metabolized in patients with impaired liver function.
No formal studies have been conducted to evaluate the effect of renal disease on the pharmacokinetics of Seasonale .
See PRECAUTIONS section – Drug Interactions.
Seasonale tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.
In a 1-year controlled clinical trial, 4 pregnancies occurred in women 18-35 years of age during 809 completed 91-day cycles of Seasonale during which no backup contraception was utilized. This represents an overall use-efficacy (typical user efficacy) pregnancy rate of 1.98 per 100 women-years of use.
Oral contraceptives are highly effective for pregnancy prevention. Table 2 lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and Norplant® Implant System, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
|Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998.|
|% of Women Experiencing an Unintended Pregnancy within the First Year of Use||% of Women Continuing Use at One Year *|
|Method (1)||Typical Use †(2)||Perfect Use ‡(3)|| |
|Copper T 380A||0.8||0.6||78|
|Norplant and Norplant-2||0.05||0.05||88|
|Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. à|
|Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception. è|