Minastrin 24 Fe (Page 4 of 6)

7.2 Effects of Combined Oral Contraceptives on Other Drugs

COCs containing ethinyl estradiol may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs.

7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Do not co-administer Minastrin 24 Fe with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.3)].

7. 4 Interference with Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion.

8.3 Nursing Mothers

When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

8.4 Pediatric Use

Safety and efficacy of Minastrin 24 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

Minastrin 24 Fe has not been studied in postmenopausal women and is not indicated in this population.

8.6 Renal Impairment

The pharmacokinetics of Minastrin 24 Fe has not been studied in subjects with renal impairment.

8.7 Hepatic Impairment

The pharmacokinetics of Minastrin 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 [ s ee Contraindications (4) and Warnings and Precautions (5.2)] .

8.8 Body Mass Index

The safety and efficacy of Minastrin 24 Fe in women with a body mass index (BMI) greater than 35 kg/m² has not been evaluated [ s ee 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 D ESCRIPTION

Minastrin 24 Fe provides an oral contraceptive regimen consisting of 24 white active chewable tablets that contain the active ingredients, followed by 4 brown non-hormonal placebo tablets as specified below:

• 24 white, round tablets each containing 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.
  
• 4 brown, round tablets each containing 75 mg ferrous fumarate

Each white active chewable tablet also contains the following inactive ingredients: acacia, lactose monohydrate, magnesium stearate, modified starch, confectioner’s sugar, talc, sucralose and spearmint flavor.

Each brown placebo tablet contains ferrous fumarate, mannitol, povidone, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, sucralose and spearmint flavor. The ferrous fumarate tablets do not serve any therapeutic purpose.

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

The chemical name of ethinyl estradiol is [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-]. The molecular weight of ethinyl estradiol is 296.40.

The empirical formula of norethindrone acetate is C₂₂ H₂₈ O₃ and the structural formula is:

The chemical name of norethindrone acetate is [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-]. The molecular weight of norethindrone acetate is 340.46.

12 CLINICAL PHARMACOLOGY

Figure 2. Mean (± Standard Deviation) Plasma Norethindrone Concentration-Time Profile Following Single-Dose Oral Administration of Minastrin 24 Fe Tablets (chewed and swallowed) to Healthy Female Volunteers under Fasting Conditions (n = 35)Figure 3. Mean (± Standard Deviation) Plasma Ethinyl Estradiol Concentration-Time Profile Following Single-Dose Oral Administration of Minastrin 24 Fe Tablets (chewed and swallowed) to Healthy Female Volunteers under Fasting Conditions (n = 35)

12.1 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.

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted with Minastrin 24 Fe.

12.3 Pharmacokinetics

Absorption In a single-dose, two-way, crossover clinical study conducted in 35 healthy, non-smoking premenopausal women under fasting condition, Minastrin 24 Fe tablet chewed and swallowed was bioequivalent to norethindrone acetate 1 mg/ethinyl estradiol 0.020 mg tablet (24-day regimen tablets) swallowed whole based on the exposure (AUC) and peak concentration (C_max ) of norethindrone and ethinyl estradiol.

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 absorbed from Minastrin 24 Fe tablets (chewed and swallowed), with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring at 1.0 hr (range: 0.7 to 2.5 hrs) and 1.3 hr (range: 1 to 2.5 hrs) post-dose, respectively. 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-dose administrations of Minastrin 24 Fe tablets (chewed and swallowed) in 35 healthy female subjects are provided in Figures 2 and 3, and Table 1.

Following multiple-dose administration of norethindrone acetate/ethinyl estradiol tablets (swallowed whole) in 17 healthy female subjects, 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 norethindrone acetate/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 2 . Mean (± Standard Deviation) Plasma Norethindrone Concentration-Time Profile Following Single-Dose Oral Administration of Minastrin 24 Fe Tablets (chewed and swallowed) to Healthy Female Volunteers under Fasting Conditions (n = 35)

Figure 3 . Mean (± Standard Deviation) Plasma Ethinyl Estradiol Concentration-Time Profile Following Single-Dose Oral Administration of Minastrin 24 Fe Tablets (chewed and swallowed) to Healthy Female Volunteers under Fasting Conditions (n = 35)

Table 1. Summary of Norethindrone (NE) and Ethinyl Estradiol (EE) Pharmacokinetics Following Single-Dose Oral Administration of Minastrin 24 Fe Tablets (chewed and swallowed) to Healthy Female Volunteers Under Fasting Conditions (n = 35)

Analyte	Arithmetic Meana (% CV) by Pharmacokinetic Parameter
	Cmax (pg/mL)	tmax (hr)	AUC(0 ± tldc ) (pg/mL•h)	AUC(0 ± inf) (pg/mL•h)	t½ (hr)
NE	10200(36)	1.03(0.67–2.50)	48620(40)	49250(40)	8.58
EE	84.7(24)	1.33(1.00–2.50)	677.5(33)	741.6(33)	9.68
Cmax = Maximum plasma concentrationtmax = Time of Cmax AUC(0 ± tldc ) = Area under plasma concentration versus time curve from 0 to tldc, the time of last determinable concentrationAUC(0 ± inf ) = Area under the plasma concentration versus time curve from time 0 to infinityt½ = Terminal phase half-life% CV = Coefficient of Variation (%)a The harmonic mean (0.693/mean terminal phase rate constant) is reported for t½ , and the median (range) is reported for tmax

Food Effect
Minastrin 24 Fe tablets may be administered without regard to meals.

A single-dose administration of norethindrone acetate/ethinyl estradiol tablets with food decreased the maximum concentration of norethindrone by 51% and increased the extent of absorption by 15% and decreased the maximum concentration of ethinyl estradiol by 51% 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 (greater than 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 norethindrone acetate/ethinyl estradiol tablets are approximately 8 hours and 14 hours, respectively.