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Crinone

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Crinone

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 Crinone, 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 Crinone are rate-limited by absorption rather than by elimination.

The bioavailability of progesterone in Crinone 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 Crinone 4% or Crinone 8%, or 45 mg or 90 mg progesterone intramuscularly. The pharmacokinetic parameters (mean ± standard deviation) are shown in Table

TABLE 1 : Single Dose Relative Bioavailability

  Crinone 4% 45 mg Intramuscular Progesterone Crinone 8% 90 mg Intramuscular Progesterone
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
t½ (hr) 55.13 ± 28.04 28.05 ± 16.87 34.8 ± 11.3 19.6 ± 6.0
F (%) 27.6 19.8
Cmax -maximum progesterone serum concentration
Cavg 0-24 -average progesterone serum concentration over 24 hours
AUC0-96 -area under the drug concentration versus time curve from 0-96 hours post dose
Tmax -time to maximum progesterone concentration
t½ -elimination half-life
F -relative bioavailability

The multiple dose pharmacokinetics of Crinone 4% and Crinone 8% administered every other day and Crinone 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 Crinone 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
t½ (hr) 45.00 ± 34.70 25.91 ± 6.15 49.87 ± 31.20 39.08 ± 12.88

Distribution

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

Metabolism

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 (5α-pregnanolone).

Excretion

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

Assisted Reproductive Technology

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 Crinone 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. Crinone 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 Crinone 8% as part of the Pilot Cycle to determine their endometrial response. Of the 55 evaluable endometrial biopsies in the Crinone 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 Crinone 8% and had a histologically “inphase” biopsy received a donor oocyte transfer. Among these 54 Crinone-treated women, clinical pregnancies (assessed about week 10 after transfer by clinical examination, ultrasound and/or -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), Crinone 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 Crinone 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, Pregnancy)

Secondary Amenorrhea

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 Crinone 4% (n = 62) or Crinone 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 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 Crinone every other day for six doses (Day 15 through Day 25 of the cycle).

In cycle 2, Crinone 4% induced bleeding in 79% of women and Crinone 8% induced bleeding in 77% of women. In the third cycle, estrogen was continued and Crinone 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 Crinone 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 Crinone 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.

Last reviewed on RxList: 9/5/2013
This monograph has been modified to include the generic and brand name in many instances.

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