Healthy
Conditions
Keywords
Healthy Subjects, Bioequivalence
Brief summary
The purpose of this study was to evaluate the relative bioavailability of a test formulation of norethindrone/ethinyl estradiol 0.4 mg/0.035 mg chewable tablets (Teva Pharmaceuticals, USA) compared to the reference listed product, FEMCON® Fe (norethindrone/ethinyl estradiol and ferrous fumarate) 0.4 mg/0.035 mg Chewable tablets (Warner Chilcott) under fed conditions in healthy, non-tobacco using, adult female subjects.
Interventions
0.4 mg/0.035 mg Chewable Tablets
DRUGFEMCON® Fe
0.4 mg/0.035 mg Chewable Tablets
Sponsors
Teva Pharmaceuticals USA
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Females, 18-45 years of age inclusive with Body Mass Index within 18-30 kg/m2 inclusive, as described in Novum Standard Operating Procedures. Female subjects must either abstain from sexual intercourse or use a reliable non-hormonal method of contraception (e.g. condom with spermicide, diaphragm, non-hormonal IUD) from at least 14 days prior to the first study dosing, throughout the study, and until 14 days after the last dose. * Normal menstrual cycle. * Good health as determined by lack of clinically significant abnormalities in health assessments performed at screening. * Signed and dated informed consent form, which meets all criteria of current FDA regulations.
Exclusion criteria
* Post menopausal or have irregular menstrual cycle. * Pregnant, lactating, or likely to become pregnant during the study. * History of any drug hypersensitivity or intolerance which, in the opinion of the Investigator, would compromise the safety of the subject or the study. * Significant history or current evidence of chronic infectious disease, system disorder, or organ dysfunction. * Presence of gastrointestinal disease or history of malabsorption within the last year. * History of psychiatric disorders occurring within the last two years that required hospitalization or medication. * Presence of a medical condition requiring regular treatment with prescription drugs. * Use of pharmacologic agents known to significantly induce or inhibit drug-metabolizing enzymes within 30 days prior to dosing. * Participation in any clinical trial within 30 days prior to dosing. * Drug or alcohol addiction requiring treatment in the past 12 months. * Donation or significant loss of whole blood (480 mL or more) within 30 days or plasma within 14 days prior to dosing. * Positive test results for HIV, Hepatitis B surface antigen, or Hepatitis C antibody. * Positive test results for drugs of abuse at screening. * Positive serum pregnancy test. * Subjects who have ever had progestational hormone implants. * Subjects who have had progestational hormone depot injections within 12 months proceeding dosing. * Subjects who are using or have used within the 3 months preceding dosing any vaginally administered estrogen or progestin-containing products. * Any personal or strong family history of estrogen- or progestogen-dependent tumors. * History of clinically significant fibrocystic breast disease. * Subjects with a history of thromboembolic disorders, myocardial infarction, or stroke. * Use of norethindrone or ethinyl estrodiol-containing oral contraceptives within 30 days of initial dosing. * Hysterectomy or oophorectomy (unilateral or bilateral) * User of tobacco or nicotine containing products within 30 days of the start of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of Norethindrone | Blood samples collected over a 60 hour period. | Bioequivalence based on Norethindrone Cmax (maximum observed concentration of drug substance in plasma). |
| AUC0-t of Norethindrone | Blood samples collected over a 60 hour period. | Bioequivalence based on Norethindrone AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration). |
| AUC0-inf of Norethindrone | Blood samples collected over a 60 hour period. | Bioequivalence based on Norethindrone AUC0-inf (area under the concentration-time curve from time zero to infinity). |
| Cmax of Ethinyl Estradiol | Blood samples collected over a 60 hour period. | Bioequivalence based on Ethinyl Estradiol Cmax (maximum observed concentration of drug substance in plasma). |
| AUC0-t of Ethinyl Estradiol | Blood samples collected over a 60 hour period. | Bioequivalence based on Ethinyl Estradiol AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration). |
| AUC0-inf of Ethinyl Estradiol | Blood samples collected over a 60 hour period. | Bioequivalence based on Ethinyl Estradiol AUC0-inf (area under the concentration-time curve from time zero to infinity). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Norethindrone/Ethinyl Estradiol (Test) First 0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol 0.4 mg/0.035 mg Chewable Tablets test product dosed in first period followed by 0.4 mg/0.035 mg FEMCON® Fe Chewable Tablets reference product dosed in the second period. | 18 |
| FEMCON® Fe (Reference) First 0.4 mg/0.035 mg FEMCON® Fe Chewable tablets reference product dosed in first period followed by 0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in the second period. | 18 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Second Intervention | Emesis within 2 x Tmax | 0 | 1 |
| Washout of 28 Days | Physician Decision | 0 | 1 |
| Washout of 28 Days | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Norethindrone/Ethinyl Estradiol (Test) First | FEMCON® Fe (Reference) First | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 18 Participants | 36 Participants |
| Race/Ethnicity, Customized Black | 12 participants | 14 participants | 26 participants |
| Race/Ethnicity, Customized Caucasian | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Hispanic | 4 participants | 3 participants | 7 participants |
| Region of Enrollment United States | 18 participants | 18 participants | 36 participants |
| Sex: Female, Male Female | 18 Participants | 18 Participants | 36 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 36 | 10 / 36 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 |
Outcome results
Primary
AUC0-inf of Ethinyl Estradiol
Bioequivalence based on Ethinyl Estradiol AUC0-inf (area under the concentration-time curve from time zero to infinity).
Time frame: Blood samples collected over a 60 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone/Ethinyl Estradiol (Test) | AUC0-inf of Ethinyl Estradiol | 2072.5423 pg*h/mL | Standard Deviation 483.0176 |
| FEMCON® Fe (Reference) | AUC0-inf of Ethinyl Estradiol | 2152.3775 pg*h/mL | Standard Deviation 517.5977 |
90% CI: [92.22, 100.84]
Primary
AUC0-inf of Norethindrone
Bioequivalence based on Norethindrone AUC0-inf (area under the concentration-time curve from time zero to infinity).
Time frame: Blood samples collected over a 60 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone/Ethinyl Estradiol (Test) | AUC0-inf of Norethindrone | 43.9982 ng*h/mL | Standard Deviation 19.4559 |
| FEMCON® Fe (Reference) | AUC0-inf of Norethindrone | 43.8819 ng*h/mL | Standard Deviation 18.8478 |
90% CI: [96.43, 105.48]
Primary
AUC0-t of Ethinyl Estradiol
Bioequivalence based on Ethinyl Estradiol AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration).
Time frame: Blood samples collected over a 60 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone/Ethinyl Estradiol (Test) | AUC0-t of Ethinyl Estradiol | 1916.2311 pg*h/mL | Standard Deviation 433.4875 |
| FEMCON® Fe (Reference) | AUC0-t of Ethinyl Estradiol | 1987.6311 pg*h/mL | Standard Deviation 478.7842 |
90% CI: [92.76, 100.77]
Primary
AUC0-t of Norethindrone
Bioequivalence based on Norethindrone AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration).
Time frame: Blood samples collected over a 60 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone/Ethinyl Estradiol (Test) | AUC0-t of Norethindrone | 37.8065 ng*h/mL | Standard Deviation 16.1921 |
| FEMCON® Fe (Reference) | AUC0-t of Norethindrone | 37.3991 ng*h/mL | Standard Deviation 15.3939 |
90% CI: [96.66, 104.66]
Primary
Cmax of Ethinyl Estradiol
Bioequivalence based on Ethinyl Estradiol Cmax (maximum observed concentration of drug substance in plasma).
Time frame: Blood samples collected over a 60 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone/Ethinyl Estradiol (Test) | Cmax of Ethinyl Estradiol | 137.6758 pg/mL | Standard Deviation 33.6231 |
| FEMCON® Fe (Reference) | Cmax of Ethinyl Estradiol | 137.8485 pg/mL | Standard Deviation 37.6177 |
90% CI: [93.69, 108]
Primary
Cmax of Norethindrone
Bioequivalence based on Norethindrone Cmax (maximum observed concentration of drug substance in plasma).
Time frame: Blood samples collected over a 60 hour period.
Population: All participants that completed the study had their samples analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone/Ethinyl Estradiol (Test) | Cmax of Norethindrone | 4.3306 ng/mL | Standard Deviation 1.7393 |
| FEMCON® Fe (Reference) | Cmax of Norethindrone | 4.2282 ng/mL | Standard Deviation 1.6696 |
90% CI: [93.08, 112.75]