Layolis Fe (Page 4 of 6)

8.4 Pediatric Use

Safety and efficacy of Layolis Fe have been established in women of reproductive age. Efficacy is expected to be the same in postpubertal adolescents under the age of 18 years as for users 18 years and older. Use of this product before menarche is not indicated.

8.5 Geriatric Use

Layolis Fe has not been studied in postmenopausal women and is not indicated in this population.

8.6 Renal Impairment

The pharmacokinetics of Layolis Fe have not been studied in subjects with renal impairment.

8.7 Hepatic Impairment

No studies have been conducted to evaluate the effect of hepatic disease on the disposition of Layolis Fe. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal [see Contraindications ( 4), and Warnings and Precautions ( 5.3)].

8.8 Body Mass Index

The safety and efficacy of Layolis Fe in women with a BMI > 35 kg/m2 have not been evaluated.

10 OVERDOSAGE

There have been no reports of serious ill effects from overdose of oral contraceptives including ingestion by children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

11 DESCRIPTION

Layolis Fe provides an oral contraceptive regimen consisting of 24 tablets that contain the active ingredients specified below, followed by four non-hormonal placebo tablets:

  • 24 light green, round tablets each containing 0.8 mg norethindrone and 0.025 mg ethinyl estradiol
  • 4 brown, round tablets each containing 75 mg ferrous fumarate

Each light green tablet also contains the following inactive ingredients: D&C Yellow No. 10 aluminum lake, FD&C Blue No. 1 aluminum lake, FD&C Yellow No. 6 aluminum lake, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium starch glycolate, spearmint flavor, sucralose and vitamin E.

Each brown, round tablet contains ferrous fumarate, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium starch glycolate, spearmint flavor and sucralose. The ferrous fumarate chewable tablets do not serve any therapeutic purpose. Ferrous fumarate chewable tablets are not USP for dissolution and assay.

The empirical formula of ethinyl estradiol is C20 H24 O2 and the chemical structure is:

Chemical structure of ethinyl estradiol.

The chemical name of ethinyl estradiol is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol,(17α)-]

The empirical formula of norethindrone is C20 H26 O2 and the chemical structure is:

Chemical structure for norethindrone.

The chemical name of norethindrone is [17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one]

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

COCs lower the risk of becoming pregnant primarily by suppressing ovulation.

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted with Layolis Fe.

12.3 Pharmacokinetics

Absorption

Norethindrone and ethinyl estradiol are absorbed with maximum plasma concentrations occurring within 2 hours after Layolis Fe administration (see Table 1). 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.

The plasma norethindrone and ethinyl estradiol pharmacokinetics following single- and multiple-dose administrations of Layolis Fe in 17 healthy female volunteers are provided in Table 1.

Following multiple-dose administration of Layolis Fe, mean maximum concentrations of norethindrone and ethinyl estradiol were increased by 126% and 14%, respectively, as compared to single-dose administration. Mean norethindrone and ethinyl estradiol exposures (AUC values) were increased by 239% and 55% respectively, as compared to single-dose administration of Layolis Fe.

Mean sex hormone binding globulin (SHBG) concentrations were increased by 170% from baseline (40.0 pg/mL; CV = 65%) to 108 pg/mL (CV = 45%) at steady-state.

Table 1. Pharmacokinetic Parameter Values Following Single and Multiple Dose Administration of Layolis Fe
Arithmetic mean parameters (%CV)
Regimen Analyte C max t max AUC 0 — 24h t 1/2 *
Day 1(Single Dose) N = 17 NE 9,840(36) 1.4(49) 41,680(47)
EE 147(25) 1.2(27) 903(18)
Day 24(Multiple Dose) N = 17 NE 22,200 (30) 1.6 (76) 141,200 (32) 10.8
EE 168(25) 1.2(35) 1,400(32) 17.1

EE = ethinyl estradiol; NE = norethindrone
%CV = coefficient of variation; Cmax = maximum plasma concentration (pg/mL);
tmax = time of the maximum measured plasma concentration (h);
AUC0-24h = area under the plasma concentration versus time curve from time 0 to 24h (pg•h/mL); t1/2 = apparent elimination half life (h)
*The harmonic mean for t1/2 is presented

Food Effect

Layolis Fe may be administered with or without food. A single-dose administration of Layolis Fe with food decreased the maximum concentration of norethindrone by 47% and increased the extent of absorption by 10-14% and decreased the maximum concentration of ethinyl estradiol by 39% but not the extent of absorption.

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 SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.

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 is metabolically converted to ethinyl estradiol, such that exposure to ethinyl estradiol following administration of 1 mg of norethindrone acetate is equivalent to oral administration of 2.8 mcg ethinyl estradiol; therefore 0.8 mg norethindrone would be equivalent to the oral administration of 2.6 mcg 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). Elimination half-lives of norethindrone and ethinyl estradiol following administration of 0.8 mg norethindrone / 0.025 mcg ethinyl estradiol tablets are approximately 11 hours and 17 hours, respectively.

Specific Populations

Pediatric Use: Safety and efficacy of Layolis Fe have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.

Geriatric Use: Layolis Fe has not been studied in postmenopausal women and is not indicated in this population.

Renal Impairment: The pharmacokinetics of Layolis Fe have not been studied in subjects with renal impairment.

Hepatic Impairment: The pharmacokinetics of Layolis Fe have not been studied in subjects with hepatic impairment. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal [see Contraindications ( 4), and Warnings and Precautions ( 5.3)].

Body Mass Index: The efficacy of Layolis Fe in women with a BMI of > 35 kg/m2 has not been evaluated.

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