Progesterone Gel For Vaginal Use Only

Assisted Reproductive Technology

In a study of 61 women with ovarian failure undergoing a donor oocyte transfer procedure receiving Prochieve® 8% twice daily, treatment-emergent adverse events occurring in 5% or more of the women are shown in Table 3.

TABLE 3 : Treatment-Emergent Advers e Events in ≥ 5% of Women Receiving Prochieve® 8% Twice Daily Study COL1620-007US (n=61)

In a second clinical study of 139 women using Prochieve® 8% once daily for luteal phase support while undergoing an in vitro fertilization procedure, treatment-emergent adverse events reported in ≥ 5% of the women are shown in Table 4.

TABLE 4 : Treatment-Emergent Advers e Events in ≥ 5% of Women Receiving Prochieve® 8% Once Daily Study COL1620-F01 (n=139)

In three studies, 127 women with secondary amenorrhea received estrogen replacement therapy and Prochieve® 4% or 8% every other day for six doses. Treatment emergent adverse events during estrogen and Prochieve® treatment that occurred in 5% or more of women are shown in Table 5.

TABLE 5 : Treatment-Emergent Adverse Events in ≥ 5% of Women Receiving Estrogen Treatment and Prochieve® Every Other Day Studies COL1620-004US, COL1620-005US, COL1620-009US

Additional adverse events reported in women at a frequency < 5% in Prochieve® ART and secondary amenorrhea studies and not listed in the tables above include:

Autonomic Nervous System–mouth dry, sweating increased

Body as a Whole–abnormal crying, allergic reaction, allergy, appetite decreased, asthenia, edema, face edema, fever, hot flushes, influenza-like symptoms, water retention, xerophthalmia

Cardiovascular, General–syncope

Central and Peripheral Nervous System–migraine, tremor

Gastro-Intestinal–dyspepsia, eructation, flatulence, gastritis, toothache

Metabolic and Nutritional–thirst

Musculo-Skeletal System–cramps legs, leg pain, skeletal pain

Neoplasm–benign cyst

Platelet, Bleeding & Clotting–purpura

Psychiatric–aggressive reactions, forgetfulness, insomnia

Red Blood Cell–anemia

Reproductive, Female–dysmenorrhea, premenstrual tension, vaginal dryness

Resistance Mechanism–infection, pharyngitis, sinusitis, urinary tract infection

Respiratory System–asthma, dyspnea, hyperventilation, rhinitis

Skin and Appendages–acne, pruritis, rash, seborrhea, skin discoloration, skin disorder, urticaria

Urinary System–cystitis, dysuria, micturition frequency

Vision Disorders–conjunctivitis

The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately.

Progesterone and progestins have been used to prevent miscarriage in women with a history of recurrent spontaneous pregnancy losses. No adequate evidence is available to show that they are effective for this purpose.

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

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

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

Progesterone is extensively bound to serum proteins (~96-99%), primarily to serum albumin and corticosteroid binding globulin.

The major urinary metabolite of oral progesterone is 5β-pregnan-3α, 20α-diol glucuronide which is present in plasma in the conjugated form only. Plasma metabolites also include 5β-pregnan-3α-ol-20-one (5β-pregnanolone) and 5α-pregnan-3α-ol-20-one (5β-pregnanolone).

Progesterone undergoes both biliary and renal elimination. Following an injection of labeled progesterone, 50-60% of the excretion of progesterone metabolites occurs via the kidney; approximately 10% occurs via the bile and feces, the second major excretory pathway. Overall recovery of labeled material accounts for 70% of an administered dose, with the remainder of the dose not characterized with respect to elimination. Only a small portion of unchanged progesterone is excreted in the bile.

Clinical Studies

In a single-center, open-label study (COL1620-007US), 99 women (aged 28-47 years) with either partial (n=84) or premature ovarian failure (n=15) who were candidates to receive a donor oocyte transfer as an Assisted Reproductive Technology (“ART”) procedure were randomized to receive either Prochieve® 8% twice daily (n=68) or intramuscular progesterone 100 mg daily (n=31). The study was divided into three phases (Pilot, Donor Egg and Treatment). The first phase of the study consisted of a test Pilot Cycle to ensure that the administration of transdermal estradiol and progesterone would adequately prime the endometrium to receive the donor egg. The second phase was the Donor Egg Cycle during which a fertilized oocyte was implanted. Prochieve® 8% was administered beginning the evening of Day 14 of the Pilot and Donor Egg cycles. Subjects with partial ovarian function also underwent a Pre-Pilot Cycle and a Pre-Donor Egg Cycle during which time they were administered only leuprolide acetate to suppress remaining ovarian function. The Pre-Pilot Cycle, Pilot Cycle, Pre-Donor Egg Cycle, and Donor Egg Cycle each lasted approximately 34 days. The third phase of the study consisted of a 10-week treatment period to maintain a pregnancy until placental autonomy was achieved.

Sixty-one women received Prochieve® 8% as part of the Pilot Cycle to determine their endometrial response. Of the 55 evaluable endometrial biopsies in the Prochieve® 8% group performed on Day 25- 27, all were histologically “in-phase”, consistent with luteal phase biopsy specimens of menstruating women at comparable time intervals. Fifty-four women who received Prochieve® 8% and had a histologically “in-phase” biopsy received a donor oocyte transfer. Among these 54 Prochieve® -treated women, clinical pregnancies (assessed about week 10 after transfer by clinical examination, ultrasound and/or β-hCG levels) occurred in 26 women (48%). Seventeen women (31%) delivered a total of 25 newborns, seven women (13%) had spontaneous abortions and two women (4%) had elective abortions.

In a second study (COL1620-F01), Prochieve® 8% was used in luteal phase support of women with tubal or idiopathic infertility due to endometriosis and normal ovulatory cycles, undergoing in vitro fertilization (“IVF”) procedures. All women received a GnRH analog to suppress endogenous progesterone, human menopausal gonadotropins, and human chorionic gonadotropin. In this multi-center, open-label study, 139 women (aged 22-38 years) received Prochieve® 8% once daily beginning within 24 hours of embryo transfer and continuing through Day 30 post-transfer. Clinical pregnancies assessed at Day 90 post-transfer were seen in 36 (26%) of women. Thirty-two women (23%) delivered newborns and four women (3%) had spontaneous abortions. (See PRECAUTIONS, subsection Pregnancy)

In three parallel, open-label studies (COL1620-004US, COL1620-005US, COL1620-009US), 127 women (aged 18-44) with hypothalamic amenorrhea or premature ovarian failure were randomized to receive either Prochieve® 4% (n=62) or Prochieve® 8% (n=65). All women were treated with either conjugated estrogens 0.625 mg daily (n=100) or transdermal estradiol (delivering 50 mcg/day) twice conjugated estrogens 0.625 mg daily (n=100) or transdermal estradiol (delivering 50 mcg/day) twice weekly (n=27).

Estrogen therapy was continuous for the entire three 28-day cycle studies. At Day 15 of the second cycle (six weeks after initiating estrogen replacement), women who demonstrated adequate response to estrogen therapy (by ultrasound) and who continued to be amenorrheic received Prochieve® every other day for six doses (Day 15 through Day 25 of the cycle).

In cycle 2, Prochieve® 4% induced bleeding in 79% of women and Prochieve® 8% induced bleeding in 77% of women. In the third cycle, estrogen was continued and Prochieve® was administered every other day beginning on Day 15 for six doses. On Day 24 an endometrial biopsy was performed. In 53 women who received Prochieve® 4%, biopsy results were as follows: 7% proliferative, 40% late secretory, 19% mid secretory, 13% early secretory, 7% atrophic, 6% menstrual endometrium, 6% inactive endometrium and 2% negative endometrium. In 54 women who received Prochieve® 8%, biopsy results were as follows: 44% late secretory, 19% mid secretory, 11% early secretory, 19% atrophic, 5% menstrual endometrium and 2% “oral contraceptive like” endometrium.