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Prescription Medications

Seasonale

SEASONALE- levonorgestrel / ethinyl estradiol
Duramed Pharmaceuticals, Inc.

799-33-100184

Iss. 7/2011

Rx only

DESCRIPTION

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 structural formula

Levonorgestrel C21 H28 O2 MW: 312.4

Ethinyl Estradiol structural formula

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.

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 changes in the endometrium (which reduce the likelihood of implantation).

Pharmacokinetics

Absorption

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%.

Table 1: Mean ± SD Pharmacokinetic Parameters Following A Single Dose Administration of Two Tablets of Seasonale® in Healthy Female Subjects Under Fasting Conditions
Analyte

AUCt

(mean ± SD)

Cmax

(mean ± SD)

Tmax

(mean ± SD)

T1/2

(mean ± SD)

Levonorgestrel

60.8 ± 25.6ng*hr/mL 5.6 ± 1.5 ng/mL 1.4 ± 0.3 hours 29.8 ± 8.3 hours

Ethinyl estradiol

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.

Distribution

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.

Metabolism

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.

Excretion

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.

SPECIAL POPULATIONS

Race

No formal studies on the effect of race on the pharmacokinetics of Seasonale were conducted.

Hepatic Insufficiency

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.

Renal Insufficiency

No formal studies have been conducted to evaluate the effect of renal disease on the pharmacokinetics of Seasonale .

Drug-Drug Interactions

See PRECAUTIONS section – Drug Interactions.

INDICATIONS AND USAGE

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.

TABLE 2 Percentage of women experiencing an unintended pregnancy during the first year of typical use and the first year of perfect use of contraception and the percentage continuing use at the end of the first year: United States.
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.
*
Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an unintended pregnancy during the first year if they do not stop use for any other reason.
Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an unintended pregnancy during the first year if they do not stop use for any other reason.
§
The percentages of women becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percentage who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
Foams, creams, gels, vaginal suppositories and vaginal film.
#
Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
Þ
With spermicidal cream or jelly.
ß
Without spermicides.
à
The treatment schedule is one dose within 72 hours after unprotected intercourse and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 2 light-orange pills), Lo/Ovral (1 dose is 4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills).
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However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced or the baby reaches six months of age.
% 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)

(4)

Chance § 85 85
Spermicides 26 6 40
Periodic abstinence 25 63
Calendar 9
Ovulation method 3
Sympto-thermal # 2
Post-ovulation 1
Withdrawal 19 4
Cap Þ
Parous women 40 26 42
Nulliparous women 20 9 56
Sponge
Parous women 40 20 42
Nulliparous women 20 9 56
Diaphragm Þ 20 6 56
Condom ß
Female (Reality) 21 5 56
Male 14 3 61
Pill 5 71
Progestin only 0.5
Combined 0.1
IUD:
Progesterone T 2.0 1.5 81
Copper T 380A 0.8 0.6 78
LNg 20 0.1 0.1 81
Depo Provera 0.3 0.3 70
Norplant and Norplant-2 0.05 0.05 88
Female sterilization 0.5 0.5 100
Male sterilization 0.15 0.10 100
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
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