Estradiol/Norethindrone Acetate Tablets, 1/0.5 mg Under Fed Conditions

Study Overview
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Brief Summary
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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 fed conditions.

Detailed Description
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Criteria for Evaluation: FDA Bioequivalence Criteria Statistical Methods: FDA Bioequivalence Statistical Methods

Official Title
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A Two-Way Crossover, Open-Label, Single-Dose, Fed, 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.

Conditions
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Healthy

Intervention / Treatment
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* Drug: Estradiol/Norethindrone acetate
* Drug: Activella®


Participation Criteria
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Eligibility Criteria
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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 ≤ 92 pmol/L and follicle-stimulating hormone (FSH) of ≥ 40 IU/L. Body Mass Index (BMI) greater than or equal to 19.0 kg/m2 and less than or equal to 30.0 kg/m2. Normal findings in the physical examination, 12-lead electrocardiogram (ECG) and vital signs. Hemoglobin ≥ 115 g/L. Normal pap smear. 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 the acceptable range unless the Principal Investigator or Sub-Investigator decides that they are not clinically significant (NCS). 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 until 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 evidenced 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 not clinically significant by the Principal Investigator or Sub-Investigator. Known history of liver, kidney, and/or gallbladder dysfunction/disease, chronic diarrhea, or inflammatory bowel diseases. 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 this study, unless deemed not clinically significant by the Principal Investigator or Sub-Investigator. Any history or evidence of psychiatric or psychological disease, unless deemed not clinically significant by the Principal Investigator or the Sub-Investigator. Any history or abnormal vaginal bleeding, unless deemed not clinically significant by the Principal Investigator or the 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 or 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 (OTC) medication or any herbal supplement within the 7 days preceding this study. Use of hormonal contraceptives, oral, transdermal, implant within 30 days before drug administration or a depot injection or progestogen drug within 1 year before the drug administration. Depot injection of any drug within 6 months. Blood draws within 56 days preceding this study, during the conduct of any clinical study at another facility, or within the lockout period specified by previous study. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational Test Product<br>Estradiol/Norethindrone Acetate Tablets, 1 mg/0.5 mg | Drug: Estradiol/Norethindrone acetate<br>* 1 mg/0.5 mg Tablets<br>* Other names: Mimvey®;|
| Active Comparator: Reference Listed Drug<br>Activella® (1 mg estradiol/0.5 mg norethindrone acetate) Tablets | Drug: Activella®<br>* 1 mg/0.5 mg Tablets<br>* Other names: Estradiol/Norethindrone acetate (generic name);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Norethindrone (Maximum Observed Concentration of Drug Substance in Plasma) | Bioequivalence based on Norethindrone Cmax. | Blood samples collected over a 36 hour period. | 
| AUC0-t of Norethindrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Bioequivalence based on Norethindrone AUC0-t. | Blood samples collected over a 36 hour period. | 
| AUC0-inf of Norethindrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Bioequivalence based on Norethindrone AUC0-inf. | Blood samples collected over a 36 hour period. | 
| Cmax of Corrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma) | Bioequivalence based on Corrected Total Estrone Cmax. | Blood samples collected over a 72 hour period. | 
| AUC0-t of Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Bioequivalence based on Corrected Total Estrone AUC0-t. | Blood samples collected over a 72 hour period. | 
| AUC0-inf of Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Bioequivalence based on Corrected Total Estrone AUC0-inf. | Blood samples collected over a 72 hour period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Uncorrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Uncorrected Total Estrone. | Blood samples collected over a 72 hour period. | 
| AUC0-t of Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Uncorrected Total Estrone. | Blood samples collected over a 72 hour period. | 
| AUC0-inf of Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Uncorrected Total Estrone. | Blood samples collected over a 72 hour period. | 
| Cmax of Uncorrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Uncorrected Unconjugated Estradiol. | Blood samples collected over a 72 hour period. | 
| AUC0-t of Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Uncorrected Unconjugated Estradiol. | Blood samples collected over a 72 hour period. | 
| AUC0-inf of Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Uncorrected Unconjugated Estradiol. | Blood samples collected over a 72 hour period. | 
| Cmax of Uncorrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Uncorrected Unconjugated Estrone. | Blood samples collected over a 72 hour period. | 
| AUC0-t of Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Uncorrected Unconjugated Estrone. | Blood samples collected over a 72 hour period. | 
| AUC0-inf of Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Uncorrected Unconjugated Estrone. | Blood samples collected over a 72 hour period. | 
| Cmax of Corrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Corrected Unconjugated Estradiol. | Blood samples collected over a 72 hour period. | 
| AUC0-t of Corrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Corrected Unconjugated Estradiol. | Blood samples collected over a 72 hour period. | 
| AUC0-inf of Corrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Corrected Unconjugated Estradiol. | Blood samples collected over a 72 hour period. | 
| Cmax of Corrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Corrected Unconjugated Estrone. | Blood samples collected over a 72 hour period. | 
| AUC0-t of Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Corrected Unconjugated Estrone. | Blood samples collected over a 72 hour period. | 
| AUC0-inf of Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Corrected Unconjugated Estrone. | Blood samples collected over a 72 hour period. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bioequivalence, Healthy Subjects