Drospirenone/Ethinyl Estradiol (3 mg/0.02 mg) Tablets Under Non-Fasting Conditions

• Sponsor: Teva Pharmaceuticals USA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01182207
• Collaborator: (none)
• Enrollment: 33
• Location: 1
• Arms: 2
• Duration (Months): 1
• Patients Per Site Per Month: 32.4

Study Details

Study Description

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 tablets) in healthy, adult subjects under non-fasting conditions.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Drospirenone/Ethinyl Estradiol (Gianvi®); Drug: YAZ®	Phase 1

Detailed Description

Criteria for Evaluation: FDA Bioequivalence Criteria

Statistical Methods: FDA Bioequivalence Statistical Methods

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Official Title: A Relative Bioavailability Study of 3 mg/0.02 mg Drospirenone/Ethinyl Estradiol Tablets Under Non-Fasting Conditions.
• Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Aug 1, 2006
• Actual Study Completion Date: Aug 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Investigational Test Product Drospirenone/Ethinyl Estradiol Tablets, 3 mg/0.02 mg	Drug: Drospirenone/Ethinyl Estradiol (Gianvi®); 3 mg/0.02 mg Tablets; Other Names: Gianvi®
Active Comparator: Reference Listed Drug YAZ® Tablets, 3 mg/0.02 mg	Drug: YAZ®; 3 mg/0.02 mg Tablets; Other Names: Drospirenone/Ethinyl Estradiol (generic name)

Outcome Measures

Primary Outcome Measures

1. Cmax of Drospirenone(Maximum Observed Concentration of Drug Substance in Plasma) [Blood samples collected over a 120 hour period.]

   Bioequivalence based on Drospirenone Cmax.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: Female
• Accepts 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 weighed at least 110 pounds.

• Subjects who were 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 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 the documentation of acceptable results were provided, both were deferred. Any abnormalities/deviations from thee 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 the study and for continued enrollment.

• Female subjects who practice an acceptable non-hormonal method of birth control as judged by the investigator(s) at least 14 days prior to Period I dosing, throughout the study, and until 14 days after Period II dosing. The acceptable non-hormonal birth control methods included: double barriers, non-hormone 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 reported 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 or 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, or diastolic blood pressure lower than 45 or over 90 mmHg were excluded from the study.

• Volunteers who had a history of thrombotic disorders, have ever had a cerebrovascular accident, or had 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 principle investigator).

• Volunteers who had a history of jaundice with previous use of oral contraceptives or any other kinds of hormonal contraceptives.

• Volunteers whose clinical laboratory test values outside the acceptable 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 medications in the 14 days prior to Period 1 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 dose administration.

• 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 blood for 4 weeks after completing the study.

• Volunteers who demonstrate a positive pregnancy screen.

• Volunteers who were currently breastfeeding.

• Subjects who had used within the 3 months preceding Period I dosing any vaginally administered estrogen or progestin containing products.

• Any volunteer who engaged in unprotected sexual intercourse during the time interval starting 14 days prior to the first period until 14 days after Period II dosing.

• Volunteers who had a hysterectomy or oophorectomy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	PRACS Institute, Ltd.	Fargo	North Dakota	United States	58104

Sponsors and Collaborators

• Teva Pharmaceuticals USA

Investigators

• Principal Investigator: Anthony R Godfrey, Pharm.D., PRACS Institute, Ltd.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT01182207
• Other Study ID Numbers: R06-0632
• First Posted: Aug 16, 2010
• Last Update Posted: Dec 8, 2010
• Last Verified: Nov 1, 2010

• Keywords provided by , ,: Bioequivalence; Healthy Subjects
• Additional relevant MeSH terms: Drospirenone; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Ethinyl Estradiol; Drospirenone and ethinyl estradiol combination; Estradiol; Polyestradiol phosphate

Study Results

Participant Flow

Arm/Group Title	Drospirenone/Ethinyl Estradiol (Test) First	YAZ® (Reference) First
Arm/Group Description	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.	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.
Period Title: First Intervention
STARTED	18	15
COMPLETED	18	14
NOT COMPLETED	0	1
Period Title: First Intervention
STARTED	18	14
COMPLETED	18	14
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	18	14
COMPLETED	17	14
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Drospirenone/Ethinyl Estradiol (Test) First	YAZ® (Reference) First	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	18	15	33
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	18 100%	15 100%	33 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	18 100%	15 100%	33 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	17 94.4%	13 86.7%	30 90.9%
Hispanic	0 0%	1 6.7%	1 3%
More than One	1 5.6%	0 0%	1 3%
American Indian	0 0%	1 6.7%	1 3%
Region of Enrollment (participants) [Number]
United States	18 100%	15 100%	33 100%

Outcome Measures

1. Primary Outcome

Title	Cmax of Drospirenone(Maximum Observed Concentration of Drug Substance in Plasma)
Description	Bioequivalence based on Drospirenone Cmax.
Time Frame	Blood samples collected over a 120 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Drospirenone/Ethinyl Estradiol (Test)	YAZ® (Reference)
Arm/Group Description	3 mg/0.02 mg Drospirenone/Ethinyl Estradiol Tablets test product dosed in either period.	3 mg/0.02 mg YAZ® Tablets reference product dosed in either period.
Measure Participants	31	31
Mean (Standard Deviation) [ng/mL]	52.77 (15.77)	53.65 (13.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Drospirenone/Ethinyl Estradiol (Test), YAZ® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	96.74
	Confidence Interval	(2-Sided) 90%; 86.82 to 107.79
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

2. Primary Outcome

Title	AUC0-t of Drospirenone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Description	Bioequivalence based on Drospirenone AUC0-t.
Time Frame	Blood samples collected over a 120 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Drospirenone/Ethinyl Estradiol (Test)	YAZ® (Reference)
Arm/Group Description	3 mg/0.02 mg Drospirenone/Ethinyl Estradiol Tablets test product dosed in either period.	3 mg/0.02 mg YAZ® Tablets reference product dosed in either period.
Measure Participants	31	31
Mean (Standard Deviation) [ng*h/mL]	889.67 (187.51)	867.10 (207.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Drospirenone/Ethinyl Estradiol (Test), YAZ® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	103.16
	Confidence Interval	(2-Sided) 90%; 101.10 to 105.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

3. Primary Outcome

Title	AUC0-inf of Drospirenone(Area Under the Concentration-time Curve From Time Zero to Infinity)
Description	Bioequivalence based on Drospirenone AUC0-inf.
Time Frame	Blood samples collected over a 120 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Drospirenone/Ethinyl Estradiol (Test)	YAZ® (Reference)
Arm/Group Description	3 mg/0.02 mg Drospirenone/Ethinyl Estradiol Tablets test product dosed in either period.	3 mg/0.02 mg YAZ® Tablets reference product dosed in either period.
Measure Participants	31	31
Mean (Standard Deviation) [ng*h/mL]	951.18 (226.13)	930.38 (236.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Drospirenone/Ethinyl Estradiol (Test), YAZ® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	102.72
	Confidence Interval	(2-Sided) 90%; 100.67 to 104.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

4. Primary Outcome

Title	Cmax of Ethinyl Estradiol(Maximum Observed Concentration of Drug Substance in Plasma)
Description	Bioequivalence based on Ethinyl Estradiol Cmax.
Time Frame	Blood samples collected over a 72 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Drospirenone/Ethinyl Estradiol (Test)	YAZ® (Reference)
Arm/Group Description	3 mg/0.02 mg Drospirenone/Ethinyl Estradiol Tablets test product dosed in either period.	3 mg/0.02 mg YAZ® Tablets reference product dosed in either period.
Measure Participants	31	31
Mean (Standard Deviation) [pg/mL]	87.95 (29.22)	91.23 (36.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Drospirenone/Ethinyl Estradiol (Test), YAZ® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	97.60
	Confidence Interval	(2-Sided) 90%; 89.45 to 106.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

5. Primary Outcome

Title	AUC0-t of Ethinyl Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Description	Bioequivalence based on Ethinyl Estradiol AUC0-t.
Time Frame	Blood samples collected over a 72 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Drospirenone/Ethinyl Estradiol (Test)	YAZ® (Reference)
Arm/Group Description	3 mg/0.02 mg Drospirenone/Ethinyl Estradiol Tablets test product dosed in either period.	3 mg/0.02 mg YAZ® Tablets reference product dosed in either period.
Measure Participants	31	31
Mean (Standard Deviation) [pg*h/mL]	1066.24 (372.97)	1079.54 (344.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Drospirenone/Ethinyl Estradiol (Test), YAZ® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	98.88
	Confidence Interval	(2-Sided) 90%; 95.62 to 102.25
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

6. Primary Outcome

Title	AUC0-inf of Ethinyl Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity)
Description	Bioequivalence based on Ethinyl Estradiol AUC0-inf.
Time Frame	Blood samples collected over a 72 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Drospirenone/Ethinyl Estradiol (Test)	YAZ® (Reference)
Arm/Group Description	3 mg/0.02 mg Drospirenone/Ethinyl Estradiol Tablets test product dosed in either period.	3 mg/0.02 mg YAZ® Tablets reference product dosed in either period.
Measure Participants	31	31
Mean (Standard Deviation) [pg*h/mL]	1155.69 (394.56)	1175.76 (358.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Drospirenone/Ethinyl Estradiol (Test), YAZ® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	98.20
	Confidence Interval	(2-Sided) 90%; 95.36 to 101.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

Adverse Events

Time Frame	Adverse event data was collected over the course of the study, which was approximately 6 weeks in duration.
Adverse Event Reporting Description	Volunteers were monitored throughout the study for any adverse experiences. AEs were collected through both solicited and unsolicited methods. The volunteers were encouraged to report signs, symptoms, and any changes in health to the clinic staff.
Arm/Group Title	Drospirenone/Ethinyl Estradiol (Test)		YAZ® (Reference)
Arm/Group Description	3 mg/0.02 mg Drospirenone/Ethinyl Estradiol Tablets test product dosed in either period.		3 mg/0.02 mg YAZ® Tablets reference product dosed in either period.
All Cause Mortality
	Drospirenone/Ethinyl Estradiol (Test)		YAZ® (Reference)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Drospirenone/Ethinyl Estradiol (Test)		YAZ® (Reference)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/33 (0%)
Other (Not Including Serious) Adverse Events
	Drospirenone/Ethinyl Estradiol (Test)		YAZ® (Reference)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/33 (63.6%)		11/33 (33.3%)
General disorders
Nausea	6/33 (18.2%)	7	4/33 (12.1%)	4
Dysmenorrhoea	4/33 (12.1%)	4	2/33 (6.1%)	2
Metrorrhagia	2/33 (6.1%)	2	3/33 (9.1%)	3
Abdominal Pain	3/33 (9.1%)	4	4/33 (12.1%)	4
Vomitting	3/33 (9.1%)	6	2/33 (6.1%)	2
Pharynogolaryngeal Pain	3/33 (9.1%)	3	0/33 (0%)	0
Headache	8/33 (24.2%)	9	3/33 (9.1%)	3
Sinus Headache	2/33 (6.1%)	2	0/33 (0%)	0
Menstrual Disorder	1/33 (3%)	1	2/33 (6.1%)	2
Stomach Discomfort	2/33 (6.1%)	2	0/33 (0%)	0
Dizziness	2/33 (6.1%)	2	4/33 (12.1%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Principal Investigator is not permitted to discuss or publish trial results.