Estradiol/Norethindrone Acetate Tablets, 1/0.5 mg Under Fasting Conditions - Full Text View

Purpose

The objective of this study was to determine and compare the rate and extent of absorption of norethindrone and unconjugated estradiol from a test formulation of Estradiol/Norethindrone Acetate Tablets, 1 mg/0.5 mg versus the reference Activella® (1 mg estradiol/0.5 mg norethindrone acetate) Tablets under fasting conditions.

Condition	Intervention	Phase
Healthy	Drug: Estradiol/Norethindrone acetate Drug: Activella®	Phase 1

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Bio-equivalence Study Intervention Model: Crossover Assignment Masking: Open Label
Official Title:	A Two-Way Crossover, Open-Label, Single-Dose, Fasting, Bioequivalence Study of Estradiol/Norethindrone Acetate Tablets, 1 mg/0.5 mg Versus Activella® (1 mg Estradiol/0.5 mg Norethindrone Acetate) Tablets in Normal, Healthy, Post-Menopausal Female Subjects

Resource links provided by NLM:

MedlinePlus related topics: Menopause

Drug Information available for: Estradiol Norethindrone acetate Norethindrone Estradiol cypionate Estradiol valerate Estradiol acetate Estradiol hemihydrate

U.S. FDA Resources

Further study details as provided by Teva Pharmaceuticals USA:

Primary Outcome Measures:

Cmax for Norethindrone(Maximum Observed Concentration of Drug Substance in Plasma) [ Time Frame: Blood samples collected over a 36 hour period. ] [ Designated as safety issue: No ]
Bioequivalence based on Norethindrone Cmax.
AUC0-t for Norethindrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) [ Time Frame: Blood samples collected over a 36 hour period. ] [ Designated as safety issue: No ]
Bioequivalence based on Norethindrone AUC0-t.
AUC0-inf for Norethindrone(Area Under the Concentration-time Curve From Time Zero to Infinity) [ Time Frame: Blood samples collected over a 36 hour period. ] [ Designated as safety issue: No ]
Bioequivalence based on Norethindrone AUC0-inf.
Cmax for Corrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Bioequivalence based on Corrected Total Estrone Cmax.
AUC0-t for Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Bioequivalence based on Corrected Total Estrone AUC0-t.
AUC0-inf for Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Bioequivalence based on Corrected Total Estrone AUC0-inf.

Secondary Outcome Measures:

Cmax for Uncorrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of Cmax values for Uncorrected Total Estrone.
AUC0-t for Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of AUC0-t values for Uncorrected Total Estrone.
AUC0-inf for Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of AUC0-inf values for Uncorrected Total Estrone.
Cmax for Uncorrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of Cmax values for Uncorrected Unconjugated Estradiol.
AUC0-t for Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of AUC0-t values for Uncorrected Unconjugated Estradiol.
AUC0-inf for Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of AUC0-inf values for Uncorrected Unconjugated Estradiol.
Cmax for Uncorrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of Cmax values for Uncorrected Unconjugated Estrone.
AUC0-t for Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of AUC0-t values for Uncorrected Unconjugated Estrone.
AUC0-inf for Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of AUC0-inf values for Uncorrected Unconjugated Estrone.
Cmax for Corrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of Cmax values for Corrected Unconjugated Estradiol.
AUC0-t for Corrected Unconjugated Estradiol.(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of AUC0-t values for Corrected Unconjugated Estradiol.
AUC0-inf for Corrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of AUC0-inf values for Corrected Unconjugated Estradiol.
Cmax for Corrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of Cmax values for Corrected Unconjugated Estrone.
AUC0-t for Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of AUC0-t values for Corrected Unconjugated Estrone.
AUC0-inf for Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) [ Time Frame: Blood samples collected over a 72 hour period. ] [ Designated as safety issue: No ]
Informational comparison of AUC0-inf values for Corrected Unconjugated Estrone.

Enrollment:	36
Study Start Date:	February 2007
Study Completion Date:	April 2007
Primary Completion Date:	April 2007 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Investigational Test Product Estradiol/Norethindrone acetate 1/0.5 mg Tablets	Drug: Estradiol/Norethindrone acetate 1/0.5 mg Tablets Other Name: Mimvey®
Active Comparator: Reference Listed Drug Activella® 1/0.5 mg Tablets	Drug: Activella® 1/0.5 mg Tablets Other Name: Estradiol/Norethindrone acetate (generic name)

Detailed Description:

Criteria for Evaluation: FDA Bioequivalence Criteria

Statistical Methods: FDA Bioequivalence Statistical Methods

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Non-smoking or smoking (up to 10 cigarettes/day), physiologically or surgically post-menopausal female within the age range of 18-65 years.
17β-estradiol serum levels of < 90 pmol/L and follicle-stimulating hormone (FSH) of > 40 IU/L.
Body Mass Index greater than or equal to 19.0 and less than or equal to 32.0.
Normal findings in the physical examination, 12-lead electrocardiogram (ECG) and vital signs.
Hemoglobin > 115 g/L
Normal Pap smear within 6 months.
Normal mammogram within 1 year for subjects who are over the age of 50 years.
Negative for drugs of abuse and alcohol.
Negative for hepatitis B surface antigen, hepatitis C and Human Immunodeficiency Virus (HIV).
No clinical laboratory values outside of the acceptable range as defined by BCR, unless the Principal Investigator or Sub-investigator decides that they are not clinically significant.
Negative for pregnancy.
Subjects who are surgically post-menopausal with an intact uterus (i.e. bilateral oophorectomy) for at least 6 months, or physiologically post-menopausal (i.e. spontaneous amenorrhea) for at least 1 year, and who will adhere to contraceptive requirements from at least 10 days before Period I check in, during the study and up to 1 month after the end of the study.
Availability of the subject for the entire study period and willingness of the subject to adhere to protocol requirements, as evidence by a signed ICF.

Exclusion Criteria:

Known history of hypersensitivity to norethindrone and estradiol combinations and/or norethindrone, and/or estradiol.
Known history or presence of cardiac, pulmonary, gastrointestinal, endocrine, musculoskeletal, neurological, or hematological diseases, malignancies, or migraines, unless deemed NCS by the Principal Investigator or Sub-investigator.
Known history of liver, kidney, and/or gallbladder dysfunction/disease, chronic diarrhea or inflammatory bowel disease.
Known history or presence of cerebrovascular diseases or venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.
Any history of stroke.
Presence of any significant physical or organ abnormality.
History of osteoporosis.
History or presence of fibrocystic breast disease.
History or presence of breast, endometrial, cervical, and/or uterine carcinoma.
Any illness during the 4 weeks before the study, unless deemed NCS by the Principal Investigator or Sub-investigator.
Any history or evidence of psychiatric or psychological disease, unless deemed NCS by the Principal Investigator or Sub-investigator.
Any history of abnormal vaginal bleeding, unless deemed NCS by the Principal Investigator or Sub-investigator.
Any history of asthma (after 12 years of age).
Evidence of pregnancy or lactation.
Any history of severe allergic reaction (including drugs, food, insect bites, environmental allergens).
Known history or presence of food allergies, or any condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
Any history of drug abuse.
Any recent history of alcohol abuse (less than 1 year).
Use of any prescription medication within 30 days preceding this study.
Use of hormone replacement therapy within 30 days before drug administration.
Use of over-the-counter medication or any herbal supplement within the 7 days preceding this study (except for spermicidal/barrier contraceptive products).
Use of hormonal contraceptives within the 30 days before drug administration or a depot injection of progestogen drug within 1 year before drug administration.
Depot injection of any drug (other than progestogen) within 6 months.
Blood draws within 56 days preceding this study, during the conduct of any clinical study at a facility other than BCR, or within the lockout period specified by a previous study conducted at BCR.
Blood donations within 56 days preceding this study.
Participation as a plasma donor in a plasmapheresis program within 7 days preceding this study.
Participation in a clinical trial with an investigational drug within 30 days preceding this study.
Intolerance to venipuncture.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01157182

Locations

Canada, Ontario
Biovail Clinical Research
Toronto, Ontario, Canada, M1L 4S4

Sponsors and Collaborators

Teva Pharmaceuticals USA

Investigators

Principal Investigator:

Paul Y Tam, M.D., F.R.C.P., F.A.C.P.

Biovail Contract Research

More Information

No publications provided

Responsible Party:	Associate Director, Biopharmaceutics, TEVA Pharmaceuticals, USA
ClinicalTrials.gov Identifier:	NCT01157182 History of Changes
Other Study ID Numbers:	3251
Study First Received:	July 2, 2010
Results First Received:	September 15, 2010
Last Updated:	November 22, 2010
Health Authority:	United States: Institutional Review Board

Keywords provided by Teva Pharmaceuticals USA:

Healthy
Bioequivalence
Post-Menopausal

Additional relevant MeSH terms:

Estradiol
Polyestradiol phosphate
Estradiol valerate
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Norethindrone
Norethindrone acetate
Estrogens
Hormones

Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Contraceptive Agents
Reproductive Control Agents
Therapeutic Uses
Contraceptive Agents, Female
Contraceptives, Oral, Synthetic
Contraceptives, Oral

ClinicalTrials.gov processed this record on May 23, 2013