A Study Comparing Estradiol Vaginal Cream to Estrace® Cream in Females With Atrophic Vaginitis

This randomized, double-blind, placebo-controlled, parallel group, multiple-site study was designed to evaluate the therapeutic efficacy and safety of a generic Estradiol Vaginal Cream USP, 0.01% (Alvogen Pine Brook LLC) compared to the FDA Reference Listed Drug (RLD), Estrace® (estradiol vaginal cream USP, 0.01%, Warner Chilcott) in patients with atrophic vaginitis. Additionally, both the Test and the RLD formulations were tested for superiority against a Placebo.

Following the 14-day screening period, patients who continued to meet the inclusion/exclusion criteria were randomized in a 2:2:1 ratio (Test: Reference: Placebo) for 7 days of treatment.

Five hundred and thirty-five (535) patients were randomized to one of the three study products as follows:

• Test: Estradiol Vaginal Cream USP, 0.01% (Alvogen Pine Brook LLC)
• Reference: Estrace® (estradiol vaginal cream USP, 0.01%) (Warner Chilcott)
• Placebo: Test product vehicle cream (Alvogen Pine Brook LLC)

Patients completed up to three clinic visits as follows:

• Visit 1 - Screening: Day -14 to Day -1
• Visit 2 - Randomization: Day 1
• Visit 3 - End of Study: Day 8, maximum Day 10

Study product was self-administered by the patient for 7 days according to the dosing instructions provided. Each patient was required to dose once daily at approximately the me of day for 7 consecutive days.

Inclusion criteria

• Signed Informed Consent that meets all criteria of current FDA regulations
• Females age: 30-75 years old inclusive who are postmenopausal.
• Postmenopausal defined as at least 12 months of spontaneous amenorrhea or at least 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/ml or at least 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy. Hysterectomy without oophorectomy if of age that investigator believes would have naturally reached 12 months of spontaneous amenorrhea.
• Baseline evaluation requirements:

• ≤5% superficial cells on vaginal smear cytology
• Vaginal pH > 5.0
• At least one patient self-assessed moderate to severe symptom of vulvar and/or vaginal atrophy (VVA) from the following list that is identified by the subject:
• Vaginal dryness
• Vaginal and/or vulvar irritation/itching
• Dysuria
• Vaginal pain associated with sexual activity*
• Vaginal bleeding associated with sexual activity (absence vs. presence)* *provided that patient is currently sexually active and plans to remain so throughout study.
• Normal breast exam at screening and mammogram completed within 9 months prior to screening in patients >40 years old.
• For women with an intact uterus, an endometrial thickness < 4 mm as determined by vaginal ultrasonography.
• Documented PAP smear conducted within previous 12 months with no findings that the Investigator believes would contraindicate the use of topical vaginal estradiol

Exclusion criteria

• Females younger than 30 years of age or older than 75 years of age
• Patients with a serum FSH level of ≤ 40mIU/ml at screening.
• Greater than 5% superficial cells on vaginal cytology.
• Vaginal pH ≤ 5
• Significant history or current evidence of chronic infectious disease, system disorder, organ disorder (including significant liver/kidney impairment) or other medical condition that in the Investigator's opinion would place the study patient at undue risk by participation or could jeopardize the integrity of the study evaluations.
• Patients with an intact uterus should have vaginal ultrasonography results to confirm an inactive endometrial lining. Patients with an endometrial thickness equal to or greater than 4mm should be excluded.
• Patients with known, suspected or current history of carcinoma of the breast. All patients over the age of 40 must have had a mammogram performed within 9 months of the study start and all patients will have a physical breast exam performed at screening.
• Patients with baseline systolic blood pressure of > 150mm Hg and/or diastolic pressure > 90 mm Hg
• Any patient with undiagnosed vaginal bleeding or significant risk factors for endometrial cancer.
• Any history of estrogen-dependent neoplasia (e.g., endometrial cancer).