Recommended Topic Related To:

Loestrin Fe

"What are birth control pills and how do they work?

Birth control pills are also known as oral contraceptives (OCs) or, simply, “the pill.” They offer protection against pregnancy by blocking the union of sperm and egg, thereby prevent"...

Loestrin 24 Fe

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

Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, because the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are rapidly absorbed from Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 4 hours postdose. 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 Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) tablets in 17 healthy female volunteers are provided in Figures 1 and 2, and Table 1.

Following multiple-dose administration of Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) tablets, mean maximum concentrations of norethindrone and ethinyl estradiol were increased by 95% and 27%, respectively, as compared to single-dose administration. Mean norethindrone and ethinyl estradiol exposures (AUC values) were increased by 164% and 51% respectively, as compared to single-dose administration of Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) tablets.

Steady-state with respect to norethindrone was reached by Day 17 and steady-state with respect to ethinyl estradiol was reached by Day 13.

Mean SHBG concentrations were increased by 150% from baseline (57.5 nmol/L) to 144 nmol/L at steady-state.

Figure 1. Mean Plasma Norethindrone Concentration-Time Profiles Following Single- and Multiple-Dose Oral Administration of Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) Tablets to Healthy Female Volunteers under Fasting Condition (n = 17)

Mean Plasma Norethindrone Concentration-Time Profiles 
  Following Single- and Multiple-Dose Oral Administration of Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol)  Tablets 
  to Healthy Female Volunteers under Fasting Condition (n = 17) - Illustration

Figure 2. Mean Plasma Ethinyl Estradiol Concentration-Time Profiles Following Single- and Multiple-Dose Oral Administration of Loestrin 24 Fe Tablets to Healthy Female Volunteers under Fasting Condition (n = 17)

Mean Plasma Ethinyl Estradiol Concentration-Time 
  Profiles Following Single- and Multiple-Dose Oral Administration of Loestrin 
  24 Fe Tablets to Healthy Female Volunteers under Fasting Condition (n = 17) - Illustration

Table 1. Summary of Norethindrone (NE) and Ethinyl Estradiol (EE) Pharmacokinetics Following Single- and Multiple-Dose Oral Administration of Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) Tablets to Healthy Female Volunteers under Fasting Condition (n = 17)

Regimen Analyte Arithmetic Meana (% CV) by Pharmacokinetic Parameter
Cmax
(pg/mL)
tmax
(hr)
AUC(0- 24)
(pg/mL•h)
Cmin
(pg/mL)

(hr)
Cavg
(pg/mL)
Day 1 (Single Dose) NE 8420 (31) 1.0 (0.7- 4.0) 33390 (40) -- -- --
EE 64.5 (27) 1.3 (0.7- 4.0) 465.4 (26) -- -- --
SHBG -- -- -- 57.5 (37)b -- --
Day 24 (Multiple Dose) NE 16400 (26) 1.3 (0.7-4.0) 88160 (30) 880 (51) 8.4 3670 (30)
EE 81.9 (24) 1.7 (1.0-2.0) 701.3 (28) 11.4 (43) 14.5 29.2 (28)
SHBG -- -- -- 144 (24) -- --
Cmax = Maximum plasma concentration; tmax = Time of Cmax ; Cmin = minimum plasma concentration at steady-state ; AUC(0-24) = Area under plasma concentration versus time curve from 0 to 24 hours ; t½ = Apparent first-order terminal elimination half-life ; Cavg = Average plasma concentration = AUC(0-24)/24 %CV = Coefficient of Variation (%); SHBG = Sex Hormone Binding Globulin (nmol/L)
aThe harmonic mean (0.693/mean apparent elimination rate constant) is reported for t½, and the median (range) is reported for tmax.
bThe SHBG concentration reported here is the pre-dose concentration.

Effect of Food: Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) tablets may be administered without regard to meals. A single-dose administration of Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) tablet with food decreased the maximum concentration of norethindrone by 11% and increased the extent of absorption by 27% and decreased the maximum concentration of ethinyl estradiol by 30% 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.

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 Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) tablets are approximately 8 hours and 14 hours, respectively.

Special Populations

Race. The effect of race on the disposition of norethindrone and ethinyl estradiol after Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) administration has not been evaluated.

Renal Insufficiency. The effect of renal disease on the disposition of norethindrone and ethinyl estradiol after Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) 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 Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) 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

Clinical Studies

In a clinical study, 743 women, 18 to 45 years of age, were treated with Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) for up to six 28-day cycles providing a total of 3,823 treatment-cycles of exposure. A total of 583 women completed 6 cycles of treatment. There were a total of 5 on-treatment pregnancies in 3,565 treatment cycles during which no backup contraception was used. The Pearl Index for Loestrin 24 Fe (norethindrone acetate and ethinyl estradiol) was 1.82.

Last reviewed on RxList: 9/18/2008
This monograph has been modified to include the generic and brand name in many instances.

A A A

Loestrin 24 Fe - User Reviews

Loestrin 24 Fe User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Loestrin 24 Fe sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Women's Health

Find out what women really need.