Healthy
Conditions
Keywords
Bioequivalence, Healthy Subjects
Brief summary
This study was designed to compare the relative bioavailability (rate and extent of absorption) of 3 mg/0.02 mg Drospirenone/Ethinyl Estradiol Tablets with that of YAZ® Tablets (by Berlex, Inc.) following a single, oral dose (2 x 3 mg/0.02 mg tablet) in healthy, adult subjects administered under fasting conditions.
Detailed description
Criteria for Evaluation: FDA Bioequivalence Criteria Statistical Methods: FDA Bioequivalence Statistical Methods
Interventions
3 mg/0.02 mg Tablets
DRUGYAZ®
3 mg/0.02 mg 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
* Subjects who were informed of the nature of the study and agreed to read, review, and sign the informed consent document prior to Period I dosing. * Subjects who completed the screening process within 28 days prior to Period I dosing. * Subjects who were healthy adult menstruating women 18 to 35 years of age, inclusive, at the time of dosing. * Subjects with a body mass index (BMI) between 19 and 30 kg/m2, inclusive, and weigh at least 110 pounds. * Subjects who were healthy as documented by the medical history, physical examination, vital sign assessments, and by general observations. The physical examination also included a gynecological exam. If the subject had completed an acceptable Pap smear and gynecological exam in the previous 12 months (prior to study Day 1) and documentation of acceptable results were provided, both were deferred. Any abnormalities/deviations from the normal range which were considered clinically relevant by the study physician and investigator were evaluated for individual cases, documented in study files, and agreed upon by the study physician and investigator prior to enrolling a volunteer in this study and for continued enrollment. * Female subjects who practiced an acceptable non-hormonal method of birth control as judged by the investigator(s) at least 14 days prior to Period I dosing and throughout the study and until 14 days after the Period II dosing. The acceptable non-hormonal birth control methods included: double barriers, non-hormonal releasing intrauterine device in place for at least 30 days prior to dosing, abstinence throughout the duration of the study, or surgically sterile for at least 6 months prior to Period I 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, or using injectable contraceptives within 6 months of Period I dosing. * Volunteers who have ever had progestational hormone implants. * Volunteers who reported any presence of history of a clinically significant disorder involving the cardiovascular, respiratory, renal, liver, gastrointestinal, immunologic, hematologic, endocrine, or neurologic system(s) or psychiatric or epilepsy disease as determined by the clinical investigator(s). * Volunteers who reported any presence or history of migraines or severe headaches. * Volunteers who had a systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 45 or over 90 mmHg were excluded from the study. * Volunteers who had a history of thrombotic disorders or have ever had cerebrovascular accident or transient ischemic attacks. * Volunteer 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 the principal investigator. * Volunteers who has a history of jaundice with previous use of oral contraceptives or any other kinds of hormonal contraceptives. * Volunteers whose clinical laboratory test values were outside the accepted reference range and when confirmed on re-examination were deemed to be clinically significant. * Volunteers who demonstrated a reactive screen for hepatitis B surface antigen, hepatitis C antibody, or HIV antibody. * Volunteers who reported a history of allergic response(s) to drospirenone/ethinyl estradiol, progestin/estrogens, or related drugs. * Volunteers who reported the use of any systemic prescription medication in the 14 days prior to Period I dosing (with the exception of hormonal contraceptives). * Volunteers who reported the use of any drug known to induce or inhibit hepatic drug metabolism in the 28 days prior to Period I dosing. * Volunteers who reported a history of clinically significant allergies including drug allergies. * Volunteers who reported a clinically significant illness during the 4 weeks prior to Period I dosing (as determined by the clinical investigators). * Volunteers who reported a history of drug or alcohol addiction or abuse within the past year. * Volunteers who demonstrated a positive drug abuse screen for the study prior to Period I dosing. * Volunteers who used tobacco products in the past 6 months. * Volunteers who reported donating greater than 150 mL of blood within 30 days prior to Period I dosing. All subjects were advised not to donate blood for 4 weeks after completing the study. * Volunteers who reported donating plasma within 30 days prior to Period I dosing. All subjects were advised not to donate plasma for 4 weeks after completing the study. * Volunteers who demonstrated a positive pregnancy screen. * Volunteers who are currently breastfeeding. * Volunteers who had used within the 3 months preceding Period I dosing and vaginally administered estrogen or progestin containing products. * Any volunteer who engaged in unprotected sexual intercourse during the time interval starting at 14 days prior to the first period and until 14 days after the Period II dosing. * Volunteers who had a hysterectomy or oophorectomy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of Drospirenone(Maximum Observed Concentration of Drug Substance in Plasma) | Blood samples collected over a 120 hour period. | Bioequivalence based on Drospirenone Cmax. |
| AUC0-t of Drospirenone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Blood samples collected over a 120 hour period. | Bioequivalence based on Drospirenone AUC0-t. |
| AUC0-inf of Drospirenone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Blood samples collected over a 120 hour period. | Bioequivalence based on Drospirenone AUC0-inf. |
| Cmax of Ethinyl Estradiol(Maximum Observed Concentration of Drug Substance in Plasma) | Blood samples collected over a 72 hour period. | Bioequivalence based on Ethinyl Estradiol Cmax. |
| AUC0-t of Ethinyl Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Blood samples collected over a 72 hour period. | Bioequivalence based on Ethinyl Estradiol AUC0-t. |
| AUC0-inf of Ethinyl Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity) | Blood samples collected over a 72 hour period. | Bioequivalence based on Ethinyl Estradiol AUC0-inf. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Drospirenone/Ethinyl Estradiol (Test) First 3 mg/0.02 mg Drospirenone/Ethinyl Estradiol Tablets test product dosed in first period followed by 3 mg/0.02 mg YAZ® Tablets reference product dosed in the second period. | 16 |
| YAZ® (Reference) First 3 mg/0.02 mg YAZ® Tablets reference product dosed in first period followed by 3 mg/0.02 mg Drospirenone/Ethinyl Estradiol test product dosed in the second period. | 16 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout of 28 Days | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Drospirenone/Ethinyl Estradiol (Test) First | YAZ® (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 | 16 Participants | 16 Participants | 32 Participants |
| Race/Ethnicity, Customized American Indian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 15 participants | 15 participants | 30 participants |
| Race/Ethnicity, Customized More than One | 1 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 16 participants | 16 participants | 32 participants |
| Sex: Female, Male Female | 16 Participants | 16 Participants | 32 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 | 11 / 32 | 11 / 32 |
| serious Total, serious adverse events | 0 / 32 | 0 / 32 |
Outcome results
Primary
AUC0-inf of Drospirenone(Area Under the Concentration-time Curve From Time Zero to Infinity)
Bioequivalence based on Drospirenone AUC0-inf.
Time frame: Blood samples collected over a 120 hour period.
Population: Analysis included 30 of 31 finished subjects. Subject 31 was excluded from the analysis population due to pre-dose levels greater than 5% for Cmax in Period 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Drospirenone/Ethinyl Estradiol (Test) | AUC0-inf of Drospirenone(Area Under the Concentration-time Curve From Time Zero to Infinity) | 866.91 ng*h/mL | Standard Deviation 228.41 |
| YAZ® (Reference) | AUC0-inf of Drospirenone(Area Under the Concentration-time Curve From Time Zero to Infinity) | 884.24 ng*h/mL | Standard Deviation 248.36 |
90% CI: [95.35, 101.7]
Primary
AUC0-inf of Ethinyl Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity)
Bioequivalence based on Ethinyl Estradiol AUC0-inf.
Time frame: Blood samples collected over a 72 hour period.
Population: Analysis included 29 of 31 finished subjects. Subject 13 was excluded from the analysis population due to pre-dose levels greater than 5% for Cmax in Period 1 and Period 2. Subject 31 was excluded from the analysis population due to pre-dose levels greater than 5% for Cmax in Period 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Drospirenone/Ethinyl Estradiol (Test) | AUC0-inf of Ethinyl Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity) | 1236.96 pg*h/mL | Standard Deviation 331.63 |
| YAZ® (Reference) | AUC0-inf of Ethinyl Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity) | 1235.91 pg*h/mL | Standard Deviation 324.28 |
90% CI: [96.07, 103.46]
Primary
AUC0-t of Drospirenone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Bioequivalence based on Drospirenone AUC0-t.
Time frame: Blood samples collected over a 120 hour period.
Population: Analysis included 30 of 31 finished subjects. Subject 31 was excluded from the analysis population due to pre-dose levels greater than 5% for Cmax in Period 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Drospirenone/Ethinyl Estradiol (Test) | AUC0-t of Drospirenone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | 814.32 ng*h/mL | Standard Deviation 200.6 |
| YAZ® (Reference) | AUC0-t of Drospirenone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | 824.41 ng*h/mL | Standard Deviation 194.63 |
90% CI: [95.66, 101.96]
Primary
AUC0-t of Ethinyl Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Bioequivalence based on Ethinyl Estradiol AUC0-t.
Time frame: Blood samples collected over a 72 hour period.
Population: Analysis included 29 of 31 finished subjects. Subject 13 was excluded from the analysis population due to pre-dose levels greater than 5% for Cmax in Period 1 and Period 2. Subject 31 was excluded from the analysis population due to pre-dose levels greater than 5% for Cmax in Period 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Drospirenone/Ethinyl Estradiol (Test) | AUC0-t of Ethinyl Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | 1145.90 pg*h/mL | Standard Deviation 322.08 |
| YAZ® (Reference) | AUC0-t of Ethinyl Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | 1155.31 pg*h/mL | Standard Deviation 309.12 |
90% CI: [94.55, 102.71]
Primary
Cmax of Drospirenone(Maximum Observed Concentration of Drug Substance in Plasma)
Bioequivalence based on Drospirenone Cmax.
Time frame: Blood samples collected over a 120 hour period.
Population: Analysis included 30 of 31 finished subjects. Subject 31 was excluded from the analysis population due to pre-dose levels greater than 5% for Cmax in Period 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Drospirenone/Ethinyl Estradiol (Test) | Cmax of Drospirenone(Maximum Observed Concentration of Drug Substance in Plasma) | 67.69 ng/mL | Standard Deviation 12.49 |
| YAZ® (Reference) | Cmax of Drospirenone(Maximum Observed Concentration of Drug Substance in Plasma) | 74.33 ng/mL | Standard Deviation 15.35 |
90% CI: [85.53, 100.03]
Primary
Cmax of Ethinyl Estradiol(Maximum Observed Concentration of Drug Substance in Plasma)
Bioequivalence based on Ethinyl Estradiol Cmax.
Time frame: Blood samples collected over a 72 hour period.
Population: Analysis included 29 of 31 finished subjects. Subject 13 was excluded from the analysis population due to pre-dose levels greater than 5% for Cmax in Period 1 and Period 2. Subject 31 was excluded from the analysis population due to pre-dose levels greater than 5% for Cmax in Period 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Drospirenone/Ethinyl Estradiol (Test) | Cmax of Ethinyl Estradiol(Maximum Observed Concentration of Drug Substance in Plasma) | 128.87 pg/mL | Standard Deviation 39.7 |
| YAZ® (Reference) | Cmax of Ethinyl Estradiol(Maximum Observed Concentration of Drug Substance in Plasma) | 126.03 pg/mL | Standard Deviation 35.74 |
90% CI: [94.36, 109.08]