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Generess Fe

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Generess 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 GENERESS Fe.

Pharmacokinetics

Absorption

Norethindrone and ethinyl estradiol are absorbed with maximum plasma concentrations occurring within 2 hours after GENERESS 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 GENERESS Fe in 17 healthy female volunteers are provided in Table 1.

Following multiple-dose administration of GENERESS 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 GENERESS 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 GENERESS Fe

Regimen Arithmetic mean parameters (%CV)
Analyte Cmax tmax AUC0-24h ta ½
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); t½ = apparent elimination half life (h)
a The harmonic mean for t½ is presented

Food Effect

GENERESS Fe may be administered with or without food. A single-dose administration of GENERESS 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 GENERESS 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: GENERESS Fe has not been studied in postmenopausal women and is not indicated in this population.

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

Hepatic Impairment: The pharmacokinetics of GENERESS 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, and WARNINGS AND PRECAUTIONS].

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

Clinical Studies

Oral Contraceptive Clinical Trial

In a one-year (thirteen 28-day cycles) multicenter, open-label clinical trial, 1,677 women 18 to 46 years of age were studied to assess the safety and efficacy of GENERESS Fe. The ethnic origin of the 1,570 treated subjects who were evaluable for efficacy was: Caucasian (72.0%), African-American (13.0%), Hispanic (11.2%) and Asian (1.8%). The weight range was 74 to 243 pounds with a mean weight of 148.8 pounds. Of treated women, 16.2% were lost to follow-up, 8.9% discontinued by withdrawing their consent and 8.5% discontinued due to an adverse event.

The pregnancy rate (Pearl Index) in 1,251 women 18 to 35 years of age was 2.01 (95% confidence interval 1.21, 3.14) pregnancies per 100 women-years of treatment based on 19 pregnancies that occurred after onset of treatment and within 7 days after the last pill in 12,297 cycles of treatment during which no back-up contraception was used.

Last reviewed on RxList: 7/15/2011
This monograph has been modified to include the generic and brand name in many instances.

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