Jolessa

JOLESSA — levonorgestrel and ethinyl estradiol
Physicians Total Care, Inc.

Rx only

11001623Revised February 2010

Jolessa (levonorgestrel / ethinyl estradiol tablets) 0.15 mg / 0.03 mg

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

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

Jolessa (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:

image of Levonorgestrel chemcial structure

Levonorgestrel C21 H28 O2 MW: 312.4

image of Ethinyl Estradiol chemical structure
(click image for full-size original)

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).

PharmacokineticsAbsorption

No specific investigation of the absolute bioavailability of Jolessa 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 Jolessa™ in Healthy Female Subjects Under Fasting Conditions
Analyte AUCt (mean ± SD) Cmax (mean ± SD) Tmax (mean ± SD) T1/2 (mean ± SD)
Levonorgestrel60.8 ± 25.6ng*hr/mL5.6 ± 1.5ng/mL1.4 ± 0.3 hours29.8 ± 8.3hours
Ethinyl estradiol1307 ± 361pg*hr/mL145 ± 45pg/mL1.6 ± 0.5 hours15.4 ± 3.2hours

The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Jolessa 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 17β-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16β-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 Jolessa 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 Jolessa was found to be about 15 hours.

SPECIAL POPULATIONS

Race

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

Hepatic Insufficiency

No formal studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Jolessa. 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 Jolessa.

Drug-Drug Interactions

See PRECAUTIONS section – Drug Interactions.

Jolessa Indications and Usage

Jolessa 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 Jolessa 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.
% 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 §8585
Spermicides ¶26640
Periodic abstinence2563
Calendar9
Ovulation method3
Sympto-thermal #2
Post-ovulation1
Withdrawal194
Cap Þ
Parous women402642
Nulliparous women20956
Sponge
Parous women402042
Nulliparous women20956
Diaphragm Þ20656
Condom ß
Female (Reality)21556
Male14361
Pill571
Progestin only0.5
Combined0.1
IUD:
Progesterone T2.01.581
Copper T 380A0.80.678
LNg 200.10.181
Depo Provera0.30.370
Norplant and Norplant-20.050.0588
Female sterilization0.50.5100
Male sterilization0.150.10100
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
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.ÞWith spermicidal cream or jelly.ßWithout spermicides.

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