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