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Lo Loestrin FE

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Lo Loestrin FE

Lo Loestrin FE

CLINICAL PHARMACOLOGY

Mechanism of Action

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

Pharmacodynamics

No specific pharmacodynamic studies were conducted with Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) .

Pharmacokinetics

Absorption

Norethindrone acetate is deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are absorbed from Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) , with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 55% for ethinyl estradiol.

The rate of norethindrone and ethinyl estradiol absorption from Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) tablets containing the combination of 1 mg norethindrone acetate and 10 meg ethinyl estradiol is slower than that from a norethindrone suspension/ethinyl estradiol solution, but the extent of absorption is equivalent.

Ethinyl estradiol bioavailability from Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) tablets containing 10 meg ethinyl estradiol alone is equivalent to that from an ethinyl estradiol solution.

The plasma norethindrone and ethinyl estradiol pharmacokinetic profiles and serum sex hormone binding globulin (SHBG) concentrations following multiple-dose administration of Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) were characterized in 15 healthy female volunteers. The mean plasma concentrations are shown below (Figures 1 and 2), and pharmacokinetic parameters are found in Table 1.

Ethinyl estradiol and norethindrone Cmax values increase by a factor of 1.4 and 1.9, respectively, following 24 days administration of Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) combination tablets as compared to single-dose administration. Ethinyl estradiol and norethindrone AUC0-24h values increase by a factor of 1.6 and 2.5, respectively, following 24 days administration of Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) combination tablets as compared to single-dose administration. Norethindrone concentrations more than double by Day 24 due to both accumulation and increased SHBG concentration. Steady state with respect to ethinyl estradiol and norethindrone is reached by Day 5 and Day 13, respectively.

Figure 1. Mean (± SD) plasma ethinyl estradiol concentration versus time profiles following single- and multiple-dose oral administration of Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) to healthy female volunteers (n = 15)

Mean (± SD) plasma ethinyl estradiol concentration versus time profiles - Illustration

Figure 2. Mean (± SD) plasma norethindrone concentration versus time profiles following single- and multiple-dose oral administration of Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) to healthy female volunteers (n = 15)

Mean (± SD) plasma norethindrone concentration versus time profiles - Illustration

Table 1. Summary of Norethindrone (NE) and Ethinyl Estradiol (EE) Pharmacokinetic Parameter Values Following Oral Administration of Lo Loestrin Fe to Healthy Female Volunteers (n=15)

Regimen Study Day   Arithmetic Meana (%CV) by Pharmacokinetic Parameter
Analyte Cmax tmax AUC0-24h Cmin Cavg
Single Dose Lo Loestrin Fe combination tabletc 1 NE 7360 (21) 1.7 (1.3-6.0) 33280 (33) -- --
EE 50.9 (27) 1.3 (1.0-6.0) 389.9 (27) -- --
SHBG -- -- -- 54.8 (33)b --
Multiple Dose Lo Loestrin Fe combination tabletc x 24 days 24 NE 13900 (34) 1.3 (0.7-3.0) 84160 (41) 917 (84) 3510 (41)
EE 71.3 (33) 1.3 (0.3-2.0) 621.3 (41) 10.0 (92) 25.9 (41)
SHBG -- -- -- 109 (38) --
Multiple Dose Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) combination tabletc x 24 days and ethinyl estradiol alone tabletd x 2 days 26 EE 49.9 (34) 1.3 (0.7-3.0) 403.6 (50) -- --
Cmax = Maximum plasma concentration (pg/mL); tmax = Time of Cmax (h); AUC0-24h = Area under plasma concentration versus time curve from 0 to 24 hours (pg-h/mL); Cmin = Minimum plasma concentration (pg/mL); Cavg = Average plasma concentration = AUC0-24h/24 (pg/mL) %CV = Coefficient of Variation (%); SHBG = Sex hormone binding globulin (nmol/L)
a The median (range) is reported for tmax
b The Cmin concentration reported for SHBG is the pre-dose concentration
c Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) combination tablets contain 1 mg norethindrone acetate and 10 meg ethinyl estradiol
d Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) ethinyl estradiol alone tablets contain 10 meg ethinyl estradiol
Food Effect

Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) tablets may be administered without regard to meals.

Administration of food with a single-dose of a Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) combination tablet did not affect the maximum concentration of norethindrone and increased the extent of absorption by 24%; it decreased the maximum concentration of ethinyl estradiol by 23% and did not affect the extent of absorption.

Administration of food with a single-dose of a Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) ethinyl estradiol alone tablet decreased the maximum concentration of ethinyl estradiol by 31% and did not affect 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 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). Elimination half-lives of norethindrone and ethinyl estradiol following administration of 1 mg norethindrone acetate/10 meg ethinyl estradiol tablets are approximately 10 hours and 16 hours, respectively.

Specific populations

The pharmacokinetics of Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) in presence of renal or hepatic impairment has not been evaluated [see Use In Specific Populations].

Clinical Studies

In a one year (thirteen 28-day cycles) multicenter open-label clinical trial, 1,270 women 18 to 35 years of age, were studied to assess the efficacy of Lo Loestrin Fe, completing the equivalent of 12,482 28-day evaluable cycles of exposure. The racial demographic of all enrolled women was: Caucasian (74.9%), African-American (11.8%), Hispanic (9.8%), Asian (1.3%), and Other (2.2%). Women with body mass index (BMI) greater than 35 mg/m2 were excluded from the study. The weight range for those women treated was 89 to 260 Ibs., with a mean weight of 150 Ibs. Among the women in the trial, 51% had not used hormonal contraception immediately prior to enrolling in this study. Of treated women, 13.7% were lost to follow-up, 10.7% discontinued due to an adverse event, and 8.9% discontinued by withdrawing their consent.

The pregnancy rate (Pearl Index [PI]) in women 18 to 35 years of age was 2.92 pregnancies per 100 women-years of use (95% confidence interval 1.94 - 4.21), based on 28 pregnancies that occurred after the onset of treatment and extending through the 7 days following the last dose of Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol, ethinyl estradiol tablets) . Cycles in which conception did not occur, but which included the use of backup contraception, were not included in the calculation of the PI. The PI includes women who did not take the drug correctly.

Last reviewed on RxList: 11/30/2010
This monograph has been modified to include the generic and brand name in many instances.

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