Estradiol/Norethindrone Acetate Tablets, 1/0.5 mg Under Fasting 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 fasting 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, 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

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 < 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.

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 1/0.5 mg Tablets | Drug: Estradiol/Norethindrone acetate<br>* 1/0.5 mg Tablets<br>* Other names: Mimvey®;|
| Active Comparator: Reference Listed Drug<br>Activella® 1/0.5 mg Tablets | Drug: Activella®<br>* 1/0.5 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 for Norethindrone(Maximum Observed Concentration of Drug Substance in Plasma) | Bioequivalence based on Norethindrone Cmax. | Blood samples collected over a 36 hour period. | 
| AUC0-t for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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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Healthy, Bioequivalence, Post-Menopausal