FEMCON Fe

FEMCON FE — norethindrone and ethinyl estradiol, and ferrous fumarate
Physicians Total Care, Inc.

Ferrous fumarate tablets are not USP for dissolution and assay.

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

DESCRIPTION

FEMCON® Fe provides a regimen for oral contraception derived from 21 white tablets composed of norethindrone and ethinyl estradiol followed by 7 brown ferrous fumarate (placebo) tablets. The chemical name for norethindrone is 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one and for ethinyl estradiol the chemical name is 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. The structural formulas are:

Norethindrone structural formula

NORETHINDRONE

Ethinyl Estradiol structural formula

ETHINYL ESTRADIOL

The active white FEMCON Fe tablets contain 0.4 mg norethindrone and 0.035 mg ethinyl estradiol, and the following inactive ingredients: dibasic calcium phosphate, lactose, magnesium stearate, maltodextrin, povidone, sodium starch glycolate, spearmint flavor and sucralose.

The brown tablets contain ferrous fumarate, microcrystalline cellulose, magnesium stereate, povidone, sodium starch glycolate, and compressible sugar. The ferrous fumarate tablets do not serve any therapeutic purpose.

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

Ethinyl estradiol and norethindrone are rapidly absorbed with maximum plasma concentrations occurring within 2 hours after FEMCON Fe administration (see Table 1). Norethindrone appears to be completely absorbed following oral administration; however, it is subject to first-pass metabolism resulting in an absolute bioavailability of approximately 65%. Large intersubject variability is reflected in a 3- to 5-fold variation in norethindrone bioavailability. Ethinyl estradiol bioavailability is approximately 43% due to small-intestinal and hepatic first-pass metabolism.

Table 1. Mean ±SD Pharmacokinetic Parameters Following Single Dose Administration of FEMCON Fe in Healthy Female Subjects Under Fasting Conditions.
*
n = 26
n = 25
Norethindrone/Ethinyl Estradiol tmax (h) Cmax (pg/mL) AUC0-∞ (pg•h/mL) t1/2 (h)
Norethindrone 0.4 mg

1.24 ± 0.40*

4210.6 ± 1628.8* 18034.9 ± 7852.9 8.6 ± 3.7
Ethinyl Estradiol 35 mcg

1.44 ± 0.33

131.4 ± 34.2

1065.8 ± 276.2

17.1 ± 4.4

Cmax = maximum plasma concentration; tmax = time to reach Cmax ; AUC = area under the curve; t1/2 = elimination half life.

Effect of Food. Single-dose administration of FEMCON Fe tablets with food decreased the maximum norethindrone and ethinyl estradiol concentration by 53% and 47%, respectively; the extent of norethindrone and ethinyl estradiol absorption (AUC values) was not affected by food administration.

Distribution

Norethindrone is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin. Ethinyl estradiol is not bound to SHBG but is highly (98.5%) bound to albumin. Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg.

Metabolism

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation; less than 5% of a norethindrone dose is excreted unchanged; greater than 50% and 20-40% of a dose is excreted in urine and feces, respectively. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites.

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 which is formed by the CYP3A4 isoform of cytochrome P450.

Excretion

Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Ethinyl estradiol and norethindrone are excreted in both urine and feces, primarily as metabolites. Ethinyl estradiol is excreted in urine and feces as glucuronides and sulfates, and about 28-43% undergoes enterohepatic circulation. The mean terminal elimination half-lives of norethindrone and ethinyl estradiol following single dose administration of FEMCON Fe are approximately 9 hours and 17 hours, respectively.

Special Populations

Race. The effect of race on the disposition of norethindrone and ethinyl estradiol after FEMCON Fe administration has not been evaluated.

Renal Insufficiency. The effect of renal disease on the disposition of norethindrone and ethinyl estradiol after FEMCON Fe administration 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 and ethinyl estradiol after FEMCON Fe administration has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function.

Drug-Drug Interactions

See PRECAUTIONS section—DRUG INTERACTIONS

INDICATIONS AND USAGE

FEMCON Fe is indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.

Oral contraceptives are highly effective. 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 implants, 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, Stewart F, 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.
*
With spermicidal cream or jelly

% of Women Experiencing an Unintended

% of Women

Method

Typical Use

Perfect Use

(4)
Chance 85 85
Spermicides 26 6 40
Periodic abstinence 25 63
Calendar 9
Ovulation Method 3
Sympto-thermal 2
Post-Ovulation 1
Cap *
Parous Women 40 26 42
Nulliparous Women 20 9 56
Sponge
Parous Women 40 20 42
Nulliparous Women 20 9 56
Diaphragm * 20 6 56
Withdrawal 19 4
Condom
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 risk of pregnancy by at least 75%
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception

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