Prochieve

PROCHIEVE- progesterone gel
Columbia Laboratories

DESCRIPTION

Prochieve® (progesterone gel) is a bioadhesive vaginal gel containing micronized progesterone in an emulsion system, which is contained in single use, one piece polyethylene vaginal applicators. The carrier vehicle is an oil in water emulsion containing the water swellable, but insoluble polymer, polycarbophil. The progesterone is partially soluble in both the oil and water phase of the vehicle, with the majority of the progesterone existing as a suspension. Physically, Prochieve® has the appearance of a soft, white to off-white gel.

The active ingredient, progesterone, is present in either a 4% or an 8% concentration (w/w). The chemical name for progesterone is pregn-4-ene-3,20-dione. It has an empirical formula of C21 H30 O2 and a molecular weight of 314.5.

The structural formula is:

Chemical Structure

Progesterone exists in two polymorphic forms. Form 1, which is the form used in Prochieve® , exists as white orthorhombic prisms with a melting point of 127-131°C.

Each applicator delivers 1.125 grams of Prochieve® gel containing either 45 mg (4% gel) or 90 mg (8% gel) of progesterone in a base containing glycerin, mineral oil, polycarbophil, carbomer 934P, hydrogenated palm oil glyceride, sorbic acid, purified water and may contain sodium hydroxide.

CLINICAL PHARMACOLOGY

Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory endometrium. Progesterone is essential for the development of decidual tissue, and the effect of progesterone on the differentiation of glandular epithelia and stroma has been extensively studied. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain the pregnancy. Normal or near-normal endometrial responses to oral estradiol and intramuscular progesterone have been noted in functionally agonadal women through the sixth decade of life. Progesterone administration decreases the circulatory levels of gonadotropins.

Pharmacokinetics

Absorption

Due to the sustained release properties of Prochieve® , progesterone absorption is prolonged with an absorption half-life of approximately 25-50 hours, and an elimination half-life of 5-20 minutes. Therefore, the pharmacokinetics of Prochieve® are rate-limited by absorption rather than by elimination.

The bioavailability of progesterone in Prochieve® was determined relative to progesterone administered intramuscularly. In a single dose crossover study, 20 healthy, estrogenized postmenopausal women received 45 mg or 90 mg progesterone vaginally in Prochieve® 4% or Prochieve® 8%, or 45 mg or 90 mg progesterone intramuscularly. The pharmacokinetic parameters (mean ± standard deviation) are shown in Table 1.

TABLE 1 Single Dose Relative Bioavailability
PROCHIEVE® 4% 45 mg Intramuscular Progesterone PROCHIEVE® 8% 90 mg Intramuscular Progesterone
Cmax — maximum progesterone serum concentrationCavg 0-24 — average progesterone serum concentration over 24 hoursAUC0-96 — area under the drug concentration versus time curve from 0-96 hours post doseTmax — time to maximum progesterone concentrationt1/2 — elimination half-lifeF — relative bioavailability
Cmax (ng/mL) 13.15±6.49 39.06±13.68 14.87±6.32 53.76±14.9
Cavg 0-24 (ng/mL) 6.94±4.24 22.41±4.92 6.98±3.21 28.98±8.75
AUC0-96 (ng∙hr/mL) 288.63±273.72 806.26±102.75 296.78±129.90 1378.91±176.39
Tmax (hr) 5.6±1.84 8.2±6.43 6.8±3.3 9.2±2.7
t1/2 (hr) 55.13±28.04 28.05±16.87 34.8±11.3 19.6±6.0
F (%) 27.6 19.8

The multiple dose pharmacokinetics of Prochieve® 4% and Prochieve® 8% administered every other day and Prochieve® 8% administered daily or twice daily for 12 days were studied in 10 healthy, estrogenized postmenopausal women in two separate studies. Steady state was achieved within the first 24 hours after initiation of treatment. The pharmacokinetic parameters (mean ± standard deviation) after the last administration of Prochieve® 4% or 8% derived from these studies are shown in Table 2.

TABLE 2 Multiple Dose Pharmacokinetics
Assisted Reproductive Technology Secondary Amenorrhea
Daily Dosing 8% Twice Daily Dosing 8% Every Other Day Dosing 4% Every Other Day Dosing 8%
Cmax (ng/mL) 15.97± 5.05 14.57 ± 4.49 13.21± 9.46 13.67 ± 3.58
Cavg (ng/mL) 8.99 ± 3.53 11.6 ± 3.47 4.05 ± 2.85 6.75 ± 2.83
Tmax (hr) 5.40 ± 0.97 3.55 ± 2.48 6.67 ± 3.16 7.00 ± 2.88
AUC0-t (ng∙hr/mL) 391.98 ±153.28 138.72 ± 41.58 242.15 ± 167.88 438.36 ± 223.36
t1/2 (hr) 45.00 ± 34.70 25.91 ± 6.15 49.87 ± 31.20 39.08 ± 12.88

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