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

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.

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.

Criteria for Evaluation: FDA Bioequivalence Criteria

Statistical Methods: FDA Bioequivalence Statistical Methods

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.