Gildess 1.5/30

GILDESS 1.5/30- norethindrone acetate and ethinyl estradiol tablet, film coated
Qualitest Pharmaceuticals

NORETHINDRONE ACETATE (1.5 mg) AND ETHINYL ESTRADIOL (0.03 mg) TABLETS, USP

(Each light green tablet contains 1.5 mg norethindrone acetate and 0.03 mg ethinyl estradiol.)

Rx only

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

DESCRIPTION

Norethindrone acetate and ethinyl estradiol tablets, USP are progestogen-estrogen combinations.

Norethindrone acetate and ethinyl estradiol tablets, USP provide a continuous dosage regimen consisting of 21 oral contraceptive tablets.

Each light green tablet contains norethindrone acetate (17 alpha-ethinyl-19-nortestosterone acetate), 1.5 mg; ethinyl estradiol (17 alpha-ethinyl-1,3,5(10)-estratriene-3, 17 beta-diol), 0.03 mg. Also contains colloidal silicon dioxide, compressible sugar, croscarmellose sodium, D&C Yellow #10 aluminum lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol 400, polyethylene glycol 8000, pregelatinized starch, sodium lauryl sulfate and Vitamin E.

The structural formulas are as follows:

This is an image of the structural formula for norethindrone acetate.This is an image of the structural formula for ethinyl estradiol.This is an image of the structural formula for norethindrone acetate.This is an image of the structural formula for ethinyl estradiol.

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

The pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been characterized; however, the following pharmacokinetic information regarding norethindrone acetate and ethinyl estradiol is taken from the literature.

Absorption

Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone (1). Norethindrone acetate and ethinyl estradiol are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol (1 to 3).

Distribution

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg (1 to 3). Plasma protein binding of both steroids is extensive (> 95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin (4).

Metabolism

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites (5). A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation (6).

Excretion

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites (5,6). Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg) (1 to 3).

Special Population

Race

The effect of race on the disposition of norethindrone acetate and ethinyl estradiol tablets have not been evaluated.

Renal Insufficiency

The effect of renal disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.

Hepatic Insufficiency

The effect of hepatic disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function.

Drug-Drug Interactions

Numerous drug-drug interactions have been reported for oral contraceptives. A summary of these is found under PRECAUTIONS, Drug Interactions.

INDICATIONS AND USAGE

Norethindrone acetate and ethinyl estradiol tablets, USP are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

TABLE I: LOWEST EXPECTED AND TYPICAL FAILURE RATES DURING THE FIRST YEAR OF CONTINUOUS USE OF A METHOD
% of Women Experiencing an Unintended Pregnancy in the First Year of Continuous Use
Method Lowest Expected* Typical**
(No contraception) (85) (85)
Oral contraceptives 3
combined 0.1 N/A***
progestin only 0.5 N/A***
Diaphragm with spermicidal cream or jelly 6 20
Spermicides alone (foam, creams, gels,vaginal suppositories, and vaginal film) 6 26
Vaginal Sponge
nulliparous 9 20
parous 20 40
Implant 0.05 0.05
Injection: depot medroxyprogesterone acetate 0.3 0.3
IUD
progesterone T 1.5 2.0
copper T 380A 0.6 0.8
LNg 20 0.1 0.1
Condom without spermicides
female 5 21
male 3 14
Cervical Cap with spermicidal cream or jelly
nulliparous 9 20
parous 26 40
Periodic abstinence (all methods) 1 to 9 25
Withdrawal 4 19
Female sterilization 0.5 0.5
Male sterilization 0.10 0.15

Adapted from RA Hatcher et al., Reference 7.

* The authors’ best guess of the percentage of women expected to experience an accidental pregnancy among couples who initiate a method (not necessarily for the first time) and who use it consistently and correctly during the first year if they do not stop for any other reason.

** This term represents “typical” couples who initiate use of a method (not necessarily for the first time), who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

*** N/A—Data not available.

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