Estradiol/Norethindrone Acetate Tablets, 1/0.5 mg Under Fed Conditions
Condition: Healthy
Intervention: Estradiol/Norethindrone acetate; Activella®
Intervention description: 1 mg/0.5 mg Tablets; 1 mg/0.5 mg Tablets
Intervention MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Norethindrone; Norethindrone Acetate; Estradiol; Polyestradiol phosphate
Phase: Phase 1
Study type: Interventional
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: Female
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Bioequivalence; Healthy Subjects

Summary:

      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.
    

Eligibility 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 ≤ 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.