Tilia Fe

TILIA FE- norethindrone acetate and ethinyl estradiol
Rebel Distributors Corp

Issued: August 2010 192205-2

Rx only

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

DESCRIPTION

Tilia™ Fe is a graduated estrophasic providing estrogen in a graduated sequence over a 21-day period with a constant dose of progestogen.

Tilia™ Fe provides for a continuous dosage regimen consisting of 21 oral contraceptive tablets and 7 ferrous fumarate tablets. The ferrous fumarate tablets are present to facilitate ease of drug administration via a 28-day regimen, are non-hormonal, and do not serve any therapeutic purpose.

Each white tablet contains 1 mg norethindrone acetate, (17α) 17-(acetyloxy)-19-norpregn-4-en-20-yn-3-one, and 20 mcg ethinyl estradiol, (17α)-19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol. The inactive ingredients present are anhydrous lactose, magnesium stearate, microcrystalline cellulose, polacrillin potassium, and povidone.

Each light-green tablet contains 1 mg norethindrone acetate and 30 mcg ethinyl estradiol. The inactive ingredients present are anhydrous lactose, magnesium stearate, microcrystalline cellulose, polacrillin potassium, and povidone. The light-green tablets also contain D&C Yellow #10 and FD&C Blue #1.

Each green tablet contains 1 mg norethindrone acetate and 35 mcg ethinyl estradiol. The inactive ingredients present are anhydrous lactose, magnesium stearate, microcrystalline cellulose, polacrillin potassium, and povidone. The green tablets also contain D&C Yellow #10 and FD&C Blue #1.

The structural formulas are as follows:

Structural formulas of Norethindrone Acetate and Ethinyl Estradiol
(click image for full-size original)

Norethindrone Acetate C22 H28 O3 M.W. 340.46 Ethinyl Es tradiol C20 H24 O2 M.W. 296.4

Each inactive, brown tablet contains microcrystalline cellulose, ferrous fumarate, magnesium stearate and sodium starch glycolate. Ferrous fumarate tablets are not USP for dissolution and assay.

Each dispenser of Tilia™ Fe, contains 5 white tablets, 7 light-green tablets, 9 green tablets, and 7 brown tablets. These tablets are to be taken in the following order: one white tablet each day for five days, then one light-green tablet each day for seven days, followed by one green tablet each day for nine days, and then one brown tablet each day for seven days.

CLINICAL PHARMACOLOGY

ORAL CONTRACEPTION

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).

In vitro and animal studies have shown that norethindrone combines high progestational activity with low intrinsic androgenicity. In humans, norethindrone acetate in combination with ethinyl estradiol does not counteract estrogen-induced increases in sex hormone binding globulin (SHBG). Following multiple-dose administration of norethindrone acetate and ethinyl estradiol tablets, serum SHBG concentrations increase two- to three-fold and free testosterone concentrations decrease by 47% to 64%, indicating minimal androgenic activity.

ACNE

Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of norethindrone acetate and ethinyl estradiol increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established.

Pharmacokinetics

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. Norethindrone acetate and ethinyl estradiol are rapidly absorbed, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 2 hours post-dose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol.

Administration of norethindrone acetate/ethinyl estradiol with a high fat meal decreases rate, but not extent, of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27% following administration with food.

Plasma concentrations of norethindrone and ethinyl estradiol following chronic administration of norethindrone acetate and ethinyl estradiol tablets to 17 women are shown below (Figure 1). Mean steady-state concentrations of norethindrone for the 1/20, 1/30, and 1/35 tablet strengths increased as ethinyl estradiol dose increased over the 21-day dose regimen, due to dose-dependent effects of ethinyl estradiol on serum SHBG concentrations (Table 1). Mean steady-state plasma concentrations of ethinyl estradiol for the 1/20, 1/30, and 1/35 tablet strengths were proportional to ethinyl estradiol dose (Table 1).

Mean Plasma Concentration vs. Time
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Table 1: Mean (SD) Steady-State Pharmacokinetic Parameters Following Chronic Administration of Norethindrone Acetate and Ethinyl Estradiol Tabletsa
Norethindrone Acetate/ Ethinyl Estradiol Dose Cycle Day C max AUC CL/F SHBG b
a Cmax = Maximum plasma concentration; AUC (0-24) = Area under the plasma concentration-time curve over the dosing interval; CL/F = Apparent oral clearance
b Mean (SD) baseline value = 55 (29) nmol/L
Norethindrone
mg/mcg ng/mL ng•hr/mL mL/min nmol/L
1/20 5 10.8 81.1 220 120
(3.9) (28.5) (137) (33)
1/30 12 12.7 102 166 139
(4.1) (32) (85) (42)
1/35 21 12.7 109 152 163
(4.1) (32) (73) (40)
Ethinyl Estradiol
mg/mcg pg/mL pg•hr/mL mL/min nmol/L
1/20 5 61.0 661 549
(16.8) (190) (171)
1/30 12 92.4 973 546
(26.9) (293) (199)
1/35 21 113 1149 568
(44) (372) (219)

No age-related differences were seen in plasma concentrations of ethinyl estradiol and norethindrone following administration of norethindrone acetate and ethinyl estradiol tablets to 119 postmenarchal women ages 15 to 48 years.

Distribution

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. 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. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis. Norethindrone acetate and ethinyl estradiol tablets increase serum SHBG concentrations two- to three fold (Table 1).

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. 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.

Excretion

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of norethindrone acetate and ethinyl estradiol tablets are approximately 13 hours and 19 hours, respectively.

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