Bioequivalence
Conditions
Keywords
Healthy Subjects
Brief summary
This study compared the relative bioavailability (rate and extent of absorption) of 0.4 mg/35 mcg Norethindrone and Ethinyl Estradiol Chewable Tablets by Teva Pharmaceuticals, USA with that of 0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets manufactured by Warner Chilcott Company, Inc., following a single oral dose (2 \* 0.4 mg/35 mcg chewable tablets) in healthy female adult volunteers administered under fasting conditions.
Interventions
0.4 mg/35 mcg Chewable Tablets
DRUGOvcon® 35 Fe
0.4 mg/35 mcg Chewable Tablets
Sponsors
Teva Pharmaceuticals USA
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
* Volunteers who have been informed of the nature of the study and agree to read, review, and sign the informed consent document prior to Period I dosing. * Volunteers who have completed the screening process within 28 days prior to Period I dosing. * Volunteers who are healthy adult women 18-35 years of age, inclusive, at the time of dosing. * Volunteers who have a body mass index (BMI) between 19-30 kg/m2, inclusive, and weight at least 110 lbs. * Volunteers who are healthy as documented by the medical history, physical examination, vital sign assessments, 12-lead electrocardiogram, clinical laboratory assessments, and by general observations. The physical examination will also include a gynecological exam. If the subject has completed an acceptable Papanicolaou smear and gynecological exam in the previous 12 months and documentation of acceptable results are provided, both will be deferred. Any abnormalities/deviations from the normal range that might be considered clinically relevant by the study physician and investigator will be evaluated for individual cases, documented in study files, and agreed upon by both the study physician and investigator prior to enrolling the volunteer in this study and for continued enrollment. * Volunteers must practice an acceptable non-hormonal birth control method as judged by the investigator(s) at least 14 days prior to Period I dosing, throughout the study, and until 14 days after second period dosing.
Exclusion criteria
* Volunteers who report receiving any investigational drug within 30 days prior to Period I dosing. * Volunteers who report taking any oral contraceptives including estrogen and progestin combined pills and progestin only pills or patch within 28 days prior to Period I dosing, using injectable contraceptives within 6 months of first period dosing. * Volunteers who have ever had progestational hormone implants. * Volunteers who report any presence or history of a clinically significant disorder involving the cardiovascular, respiratory, renal, gastrointestinal, immunologic, hematologic, endocrine, or neurologic systems or psychiatric disease as determined by the clinical investigator(s). * Volunteers who report any presence or history of migraines or severe headaches. * Volunteers who have systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 45 or over 90 mmHg will be excluded from the study. * Volunteers who have a history of thrombotic disorders or have ever had cerebrovascular accident or transient ischemic attacks. * Volunteers with a history of breast cancer or undiagnosed breast nodules, active malignancies or undiagnosed vaginal bleeding. * Volunteers having other conditions that may be aggravated by fluid retention (as determined by principal investigator). * Volunteers who have a history of jaundice with previous use of oral contraceptives or any other kinds of hormonal contraceptives. * Volunteers whose clinical laboratory test values fall outside the accepted reference range and when confirmed on re-examination is deemed to be clinically significant. * Volunteers who demonstrate a reactive screen for hepatitis B surface antigen, hepatitis C antibody, or HIV antibody. * Volunteers who report a history of allergic response(s) to norethindrone/ethinyl estradiol or progestin/estrogens or related drugs. * Volunteers who report the use of any systemic prescription medication in the 14 days prior to Period I dosing (with the exception of hormonal contraceptives). * Volunteers with a history of clinically significant allergies including drug allergies. * Volunteers who report a clinically significant illness during the 4 weeks prior to Period I dosing (as determined by the clinical investigators). * Volunteers who report a history of drug or alcohol addiction or abuse within the past year. * Volunteers who demonstrate a positive drug abuse screen for this study prior to Period I dose administration. * Volunteers who currently use or have used tobacco products within 30 days prior to Period I dosing. * Volunteers who report donating greater that 150 mL of blood within 30 days prior to Period I dosing. All subjects will be advised not to donate blood for 4 weeks after completing the study. * Volunteers who report donating plasma within 30 days prior to Period I dosing. All subjects will be advised not to donate plasma for 4 weeks after completing the study. * Volunteers who demonstrate a positive pregnancy screen. * Volunteers who are currently pregnant of breastfeeding. * Volunteers who are using or have used within the 3 months preceding Period I dosing any vaginally administered estrogen or progestin-containing products. * Any volunteer who engages in unprotected sexual intercourse during the time interval starting 14 days prior to first period dosing and until 14 days after the Period II dosing. * Volunteers who have had a hysterectomy or oophorectomy (unilateral or bilateral).
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/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in first period followed by 0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in the second period. | 18 |
| Ovcon® 35 Fe (Reference) First 0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in first period followed by 0.4 mg/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in the second period. | 18 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Adverse Event | 1 | 0 |
| Washout Period of 28 Days | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Norethindrone/Ethinyl Estradiol (Test) First | Ovcon® 35 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 American Indian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 18 participants | 17 participants | 35 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 | 14 / 36 | 12 / 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: 34 out of 36 subjects completed the study. Subjects 13 \& 35 were excluded from the statistical analysis for Ethinyl Estradiol due to pre-dose concentrations greater than 5% of Cmax; therefore analysis included 32 data sets.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone/Ethinyl Estradiol (Test) | AUC0-inf of Ethinyl Estradiol | 2129.43 pg*h/mL | Standard Deviation 560.04 |
| Ovcon® 35 Fe (Reference) | AUC0-inf of Ethinyl Estradiol | 2131.84 pg*h/mL | Standard Deviation 545.91 |
90% CI: [94.91, 104.5]
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 | 48.67 ng*h/mL | Standard Deviation 34.36 |
| Ovcon® 35 Fe (Reference) | AUC0-inf of Norethindrone | 45.43 ng*h/mL | Standard Deviation 27.03 |
90% CI: [95.73, 108.62]
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: 34 out of 36 subjects completed the study. Subjects 13 \& 35 were excluded from the statistical analysis for Ethinyl Estradiol due to pre-dose concentrations greater than 5% of Cmax; therefore analysis included 32 data sets.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone/Ethinyl Estradiol (Test) | AUC0-t of Ethinyl Estradiol | 1976.72 pg*h/mL | Standard Deviation 518.96 |
| Ovcon® 35 Fe (Reference) | AUC0-t of Ethinyl Estradiol | 1989.82 pg*h/mL | Standard Deviation 475.3 |
90% CI: [93.89, 103.97]
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 | 43.83 ng*h/mL | Standard Deviation 30.5 |
| Ovcon® 35 Fe (Reference) | AUC0-t of Norethindrone | 40.73 ng*h/mL | Standard Deviation 22.41 |
90% CI: [96.74, 111.88]
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: 34 out of 36 subjects completed the study. Subjects 13 \& 35 were excluded from the statistical analysis for Ethinyl Estradiol due to pre-dose concentrations greater than 5% of Cmax; therefore analysis included 32 data sets.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Norethindrone/Ethinyl Estradiol (Test) | Cmax of Ethinyl Estradiol | 230.56 pg/mL | Standard Deviation 74.02 |
| Ovcon® 35 Fe (Reference) | Cmax of Ethinyl Estradiol | 237.00 pg/mL | Standard Deviation 62.9 |
90% CI: [90.04, 102.86]
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 | 10.94 ng/mL | Standard Deviation 5.22 |
| Ovcon® 35 Fe (Reference) | Cmax of Norethindrone | 10.00 ng/mL | Standard Deviation 4.13 |
90% CI: [100.91, 115.24]