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.
Cmax of Uncorrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma)AUC0-t of Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
AUC0-inf of Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
Cmax of Uncorrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma)
AUC0-t of Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
AUC0-inf of Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity)
Cmax of Uncorrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma)
AUC0-t of Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
AUC0-inf of Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
Cmax of Corrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma)
AUC0-t of Corrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
AUC0-inf of Corrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity)
Cmax of Corrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma)
AUC0-t of Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
AUC0-inf of Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
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.
