Vagifem (Estradiol Vaginal) - Description and Clinical Pharmacology

Description

VAGIFEM^® (estradiol vaginal tablets) are small, white, film-coated tablets containing 25.8µg of estradiol hemihydrate equivalent to 25µg of estradiol.

Each tablet contains the following inactive ingredients: hypromellose, lactose monohydrate, maize starch and magnesium stearate. The film coating contains hypromellose and polyethylene glycol. Each white tablet is 6 mm in diameter and is placed in a disposable applicator. Each tablet-filled applicator is packaged separately in a blister pack.

17ß-estradiol hemihydrate is a white, almost white or colorless crystalline solid, chemically described as estra-1,3,5 (10)-triene-3,17 diol.

The chemical formula is C₁₈H₂₄O₂•½ H2O with a molecular weight of 281.4.

The structural formula is:

Clinical Pharmacology

In vivo estrogens diffuse through cell membranes, distribute throughout the cell, bind to and activate the estrogen receptors, thereby eliciting their biological effects. Estrogen receptors have been identified in tissue of the reproductive tract, breast, pituitary, hypothalamus, liver and bone of women. The estrogen contained in VAGIFEM, 17 ß-estradiol is chemically and biologically identical to the endogenous human 17 ß-estradiol and is, therefore, classified as a human estrogen. Estrogens regulate growth, differentiation and functioning of many different tissues within and outside of the reproductive system. Estrogens are intricately involved with other hormones, especially progesterone, and during the ovulatory phase of the menstrual cycle cause proliferation of the endometrium. Most of the activity of estrogens appear to be exerted via estrogen receptors in target cells of tissues of the woman’s reproductive tract: breast, pituitary, hypothalamus, brain, liver, and bone. The steroid-receptor complex is bound to the cell’s DNA and induces synthesis of specific proteins. Maturation of the vaginal epithelium is dependent on estrogen as it increases the number of superficial and intermediate cells as compared with basal cells. Estrogen keeps the pH of the vagina at approximately 4.5 which enhances normal bacterial flora, predominately, Lactobacillus döderlein.

Pharmacokinetics

Absorption

Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism.

A single-center, randomized, double-blind comparison study conducted in the U.S. showed that vaginal application of VAGIFEM^® over a 12-week course demonstrated a mean Cmax of estradiol of 50 pg/mL and that there was no significant accumulation of estradiol as measured by the AUC 0-24 (See Table 1 below).

Table 1: MEAN (±STANDARD DEVIATION) PHARMACOKINETIC PARAMETERS FOR ESTRADIOL (Uncorrected for base line)

	Timepoint
	Day 1	Day 14	Day 84
PK Parameter:
AUC (pg.hr/mL)	538 (±265)	567 (±246)	563 (±341)
Cmax (pg/mL)	51 (±34)	47 (±21)	49 (±27)

Distribution

Circulating, unbound estrogens are known to modulate pharmacological response. Estrogens circulate in the blood bound to sex-hormone binding globulin (SHBG) and albumin. A dynamic equilibrium exists between the conjugated and the unconjugated forms of estradiol and estrone, which undergo rapid interconversion.

Metabolism

Exogenously-delivered or endogenously-derived estrogens are primarily metabolized in the liver to estrone and estriol, which are also found in the systemic circulation. VAGIFEM intravaginal administration avoids first-pass metabolism that occurs with oral estrogens.

The levels of E1 seen during 12 weeks of VAGIFEM administration do not show any accumulation of E1, and the observed values are within the postmenopausal range. See Table 2 below.

Table 2: MEAN (±STANDARD DEVIATION) PHARMACOKINETIC PARAMETERS FOR ESTRONE (Uncorrected for base line)

	Timepoint
	Day 1	Day 1 4	Day 84
E1:
AUC (pg.hr/mL)	649 (±230)	744 (±267)	681 (±271)
Cmax (pg/mL)	35 (±12)	39 (±13)	35 (±12)

Excretion

Estrogen metabolites are primarily excreted in the urine as glucuronides and sulfates.

Drug-Drug Interactions

No formal drug-drug interaction studies have been done with VAGIFEM.

Clinical Studies

A placebo-controlled comparison study was done in the U.S., in which 230 patients were randomized to receive either placebo, VAGIFEM, or 10µg estradiol vaginal tablets. Patients inserted one tablet intravaginally each day for 14 days, then one tablet twice weekly for the remaining 10 weeks. All patients were assessed for vaginal symptoms. VAGIFEM^® was superior to placebo in the relief of symptoms of the dryness, soreness, and irritation associated with atrophic vaginitis. This change of symptoms was seen at Week 7 and was maintained throughout to Week 12. (See Figure 1)

An open, controlled comparison study was done in Canada in which 159 patients were randomized to receive either VAGIFEM or the conjugated estrogen vaginal cream, comparator drug. Two (2) grams (~ 1.25 mg conjugated estrogens) of the comparator drug, which is the highest approved dose, was given daily for 3 weeks, withheld for 1 week, then repeated cyclically (3 weeks on, 1 week off) for up to 24 weeks; VAGIFEM was administered daily for 2 weeks, then twice weekly for the remaining 22 weeks. Of all patients entering into treatment phase of the study 10% of patients discontinued their treatment in the VAGIFEM group and 32% discontinued their treatment in the comparator group. In this study, patients were assessed for relief of symptoms. VAGIFEM 25µg was not less effective than the approved comparator product at the 2.0 gm dose in the relief of symptoms.

Symptoms of dryness, soreness, and irritation were rated as 0 = none, 1 = mild, 2 = moderate and 3 = severe. The average severity score of the three symptoms over time for the placebo controlled and comparator studies are shown in the following figures:

Figure 1 (Placebo controlled)

Figure 2 (Comparator)

The endometrium was evaluated at the end of each study by endometrial biopsy. See Tables 3 & 4 below.

Table 3: ENDOMETRIAL BIOPSY RESULTS COMPARING VAGIFEM WITH PLACEBO OVER 12 WEEKS OF TREATMENT (US Trial)

	VAGIFEM	Placebo
Total Number of Patients enrolled	91	47
Patients with uterus (non- hysterectomized)	48	24
Total Biopsies	32	21
Atrophic Endometrium	27 (84%)	18 (86%)
Weakly Proliferative	0 (0%)	0 (0%)
Proliferative	1 (3%)	0 (0%)
Simple Hyperplasia	1 (3%)	0 (0%)
Complex Hyperplasia	0 (0%)	0 (0%)
Insufficient Tissue	3 (9%)	3 (14%)

Table 4: ENDOMETRIAL BIOPSY RESULTS COMPARING VAGIFEM TO COMPARATOR GIVEN OVER 24 WEEKS

	VAGIFEM	Placebo
Total Number of Patients enrolled	80	79
Patients with uterus (non- hysterectomized)	80	79
Total Biopsies	49	49
Atrophic Endometrium	34 (68%)	15 (30%)
Weakly Proliferative	0 (0%)	4 (8%)
Proliferative	1 (2%)	7 (14%)
Simple Hyperplasia	0 (0%)	1 (2%)
Complex Hyperplasia	0 (0%)	1 (2%)
Insufficient Tissue	14 (28%)	21 (42%)