Blisovi 24 Fe: Package Insert and Label Information (Page 3 of 5)
8.5 Geriatric Use
Blisovi 24 Fe has not been studied in postmenopausal women and is not indicated in this population.
8.6 Hepatic Impairment
The pharmacokinetics of Blisovi 24 Fe has not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.2)].
8.7 Renal Impairment
The pharmacokinetics of Blisovi 24 Fe has not been studied in women with renal impairment.
8.8 Body Mass Index
The safety and efficacy of Blisovi 24 Fe in women with a body mass index (BMI) > 35 kg/m2 has not been evaluated [see CLINICAL STUDIES (14)].
10 OVERDOSAGE
There have been no reports of serious ill effects from overdose of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.
11 DESCRIPTION
Blisovi 24 Fe is a combination oral contraceptive for oral administration consisting of active tablets containing norethindrone acetate, a progestin, and ethinyl estradiol, an estrogen, and placebo tablets containing ferrous fumarate, which serve no therapeutic purpose.
- Each active white tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol. Inactive ingredients include acacia, confectioner’s sugar, corn starch, lactose monohydrate, magnesium stearate and talc.
- Each placebo brown tablet contains 75 mg ferrous fumarate, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and sucrose. The ferrous fumarate tablets do not serve any therapeutic purpose. Ferrous fumarate tablets are not USP for dissolution.
The chemical name of ethinyl estradiol is 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. The empirical formula of ethinyl estradiol is C20 H24 O2 and the structural formula is
The chemical name of norethindrone acetate is 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate. The empirical formula of norethindrone acetate is C22 H28 O3 and the structural formula is:
“FDA approved dissolution test specifications differ from USP”
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
CHCs prevent pregnancy primarily by suppressing ovulation.
12.2 Pharmacodynamics
No specific pharmacodynamic studies were conducted with Blisovi 24 Fe.
12.3 Pharmacokinetics
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 Blisovi 24 Fe 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 Blisovi 24 Fe tablets in 17 healthy female volunteers are provided in Figures 2 and 3, and Table 3.
Following multiple-dose administration of Blisovi 24 Fe 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 Blisovi 24 Fe 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 2. Mean Plasma Norethindrone Concentration-Time Profiles Following Single- and Multiple-Dose Oral Administration of Blisovi 24 Fe Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17)
Figure 3. Mean Plasma Ethinyl Estradiol Concentration-Time Profiles Following Single- and Multiple-Dose Oral Administration of Blisovi 24 Fe Tablets to Healthy Female Volunteers Under Fasting Condition (n = 17)
| Regimen | Analyte | Arithmetic Mean *(% CV ) by Pharmacokinetic Parameter | |||||
| Cm a x ( pg / mL ) | tm a x ( hr ) | AUC ( 0 t o 2 4 ) ( pg / mL ● h ) | Cm i n ( pg / mL ) | t1 / 2 ( hr ) | Ca v g ( pg / mL ) | ||
| NE | 8420 (31) | 1.0 (0.7 to 4.0) | 33390 (40) | — | — | — | |
| Day 1(SingleDose) | EE | 64.5 (27) | 1.3 (0.7 to 4.0) | 465.4 (26) | — | — | — |
| SHBG | — | — | — | 57.5 (37)† | — | — | |
| NE | 16400 (26) | 1.3 (0.7 to 4.0) | 88160 (30) | 880 (51) | 8.4 | 3670 (30) | |
| Day 24(MultipleDose) | EE | 81.9 (24) | 1.7 (1.0 to 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 to 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 to 24)/24
% CV = Coefficient of Variation (%)
SHBG = Sex Hormone Binding Globulin (nmol/L)
A single-dose administration of Blisovi 24 Fe 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 Blisovi 24 Fe tablets are approximately 8 hours and 14 hours, respectively.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
[See WARNINGS AND PRECAUTIONS (5.2, 5.11]
14 CLINICAL STUDIES
In an active-controlled clinical trial, 743 women 18 to 45 years of age were studied to assess the efficacy of Blisovi 24 Fe, for up to six 28-day cycles. The racial demographic of women randomized to Blisovi 24 Fe was: 69.5% Caucasian, 15.5% African-American, 10.4% Hispanic, 2.3% Asian and 2.3% Native American/Other. Women with body mass index (BMI) greater than 35 mg/m2 were excluded from the study. The weight range for those women treated was 90 to 260 pounds, with a mean weight of 147 pounds. Among the women in the study randomized to Blisovi 24 Fe, 38.9% had not used hormonal contraception immediately prior to enrolling in this study.
A total of 583 women completed 6 cycles of treatment. There were a total of 5 on-treatment pregnancies among women aged 18 to 45 years in 3,565 treatment cycles during which no back-up contraception was used. The Pearl Index for Blisovi 24 Fe was 1.82 (95% confidence interval 0.59 to 4.25).
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
Blisovi 24 Fe is available in a blister pack (NDC 68180-864-71) containing 28 tablets packed in a pouch (NDC 68180-864-71). Such three pouches are packaged in a carton (NDC 68180-864-73).
Each blister pack (28 tablets) contains in the following order:
- 24 white to off-white, round, flat face beveled edged (active) tablets debossed with “LU” on one side and “N21” on the other side and each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.
- 4 brown mottled, round, flat face beveled edge (non-hormonal placebo) tablets debossed with “LU” on one side and “M22” on the other side and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose.
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