Information for the Patient
Crinone
Pharmacology
Crinone 8% (progesterone gel) is a bioadhesive vaginal gel containing micronized progesterone in a diluted emulsion system. The carrier vehicle is a oil-in-water emulsion containing the water swellable, but insoluble polymer, polycarbophil. Physically, Crinone has the appearance of a soft, white to off-white gel packed in single-use applicators designed for vaginal administration.
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 i.m. progesterone have been noted in functionally agonadal women through the sixth decade of life. Progesterone administration decreases the circulatory level of gonadotropins.
The release of progesterone from progesterone vaginal gel 8% has been investigated in vitro.
Results indicate that approximately 65% of the progesterone is released from the gel within 24 hours, 87% is released at 48 hours, and 96% is released by 72 hours.
The pharmacokinetics of progesterone vaginal gel are rate-limited by absorption rather than by elimination. Due to Crinone's bioadhesive and sustained release properties, progesterone absorption is prolonged with an absorption half-life of approximately 25 to 50 hours, and an elimination half-life of 5 to 20 minutes.
The bioavailability of progesterone in Crinone was determined relative to progesterone administered orally and vaginally. In a parallel group study, 18 healthy, estrogenized postmenopausal women received single doses of either 90 mg of progesterone vaginally in Crinone 8%, 100 mg of progesterone orally in a capsule, or 100 mg of progesterone vaginally in a capsule. After Crinone 8% administration, the mean area under the plasma concentration curve (AUC) was 157.83 ng·h/mL indicating a similar relative bioavailability to the vaginal capsule (247.41 ng·h/mL) and more than 20 times higher than the bioavailability of the oral capsule (6.74 ng·h/mL). These data suggested that when progesterone is given orally, up to 95% of the dose is eliminated by first-pass metabolism. The mean plasma concentrations following oral progesterone capsules and vaginal progesterone vaginal gel administration were 1.04 and 3.49 ng/mL at 2 hours postdose (Cmax for oral capsules), and 0 and 8.15 ng/mL at 8 hours (Cmax for progesterone vaginal gel), respectively. The variability in bioavailability was lower with progesterone vaginal gel than with the capsule administered vaginally, indicating a more consistent delivery of progesterone.
The pharmacokinetics of progesterone vaginal gel 90 mg administered twice daily for 12 days were studied in 10 healthy, estrogenized postmenopausal women. The average peak serum concentration achieved was 14.6 ng/mL 4 hours after administration. The average steady-state concentration was 11.6 ng/mL. Steady state was achieved within the first 24 hours after initialization of treatment. Upon attainment of steady state, the disposition of progesterone administered by progesterone vaginal gel suggests zero order release and absorption kinetics.
Progesterone vaginal gel 90 mg was applied twice daily in 50 women without ovarian function undergoing estrogen/progesterone vaginal gel physiologic hormone replacement cycles designed for an Assisted Reproductive Technology (“ART”) procedure. Endometrial biopsies performed on Day 25 to 27 were histologically in-phase, consistent in morphological evaluation to natural luteal phase biopsy specimens at comparable time intervals. In this study, progesterone vaginal gel was administered beginning the evening of Day 14 through Day 27 of the replacement cycle and continued if a pregnancy occurred, for about 10 to 12 weeks. Clinical pregnancies occurred in 48% of the women treated with progesterone vaginal gel as part of their regimen.
In clinical pharmacodynamic studies, vaginal application of progesterone vaginal gel containing 45, 90 or 180 mg of progesterone every other day for a total of 6 or 7 applications resulted in mean steady-state plasma progesterone concentrations of 1 to 4 ng/mL. Progesterone vaginal gel was administered in these studies from Day 15 through Day 25 of a replacement cycle. Despite the relatively low plasma progesterone concentrations, progesterone vaginal gel induced a secretory transformation of the endometrium in 35 of the 36 women studied. The apparent discrepancy between the low plasma progesterone concentrations and the pronounced endometrial effects observed in these studies suggest a preferential distribution of transvaginally administered progesterone or a “First Uterine-Pass Effect”.
Indications
For luteal phase support in induced cycles such as in vitro fertilization (IVF) cycles including in oocyte donation recipient.
Precautions
No drug interactions have been reported with progesterone vaginal gel in clinical studies.
While progesterone gel is administered vaginally, detectable amounts of other orally administered progesterone have been identified in the milk of mothers receiving progesterone. The possible effects of progesterone on the nursing infant have not been determined.
Safety and effectiveness in females before menarche have not been established. As progesterone vaginal gel is indicated for use in women who are post-menarcheal, pediatric use is not applicable.
The pretreatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear.
Because progestins may cause some degree of fluid retention, conditions which might be influenced by this factor (e.g., epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation.
The pathologist should be advised of progesterone therapy when relevant specimens are submitted.
The product should not be used concurrently with other local intravaginal therapy. If other local intravaginal therapy is to be used concurrently, there should be at least a 6-hour period before or after progesterone vaginal gel administration.
In cases of breakthrough bleeding, as in all cases of irregular bleeding per vaginum, nonfunctional causes should be borne in mind. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures should be undertaken.
Progesterone vaginal gel has been used to successfully support embryo implantation and maintain pregnancies through its use as part of ART treatment regimens. In 50 patients receiving donor oocyte transfer procedures, clinical pregnancies occurred in 48% of those receiving progesterone vaginal gel. One woman had an elective termination of pregnancy at 19 weeks due to congenital malformations. Other deliveries resulted in normal newborns. Progesterone vaginal gel has been used in the luteal phase support of patients undergoing in vitro fertilization (IVF) procedures. In a clinical study, 139 patients received progesterone vaginal gel (90 mg) once daily beginning on the day of embryo transfer and continuing through Day 30 post-transfer. The IVF success rates for pregnancies at Day 90 (26% of those transferred) and deliveries (23% of those transferred) were similar to success rates observed in larger IVF studies. Of the 47 newborns delivered, 1 suffered from a teratoma associated with a cleft palate and another from respiratory distress syndrome. Forty-four newborns were normal and 1 was lost to follow-up. The resulting rate of malformations was similar to that reported in the literature for pregnancies following IVF procedures as in normal pregnancies.
Supplied
Each single-use, one piece, disposable, white polyethylene vaginal applicator with a twist-off top, contains: progesterone 90 mg (8%). Each applicator contains 1.45 g of gel and delivers 1.125 g of gel. Nonmedicinal ingredients: carbomer 974P, glycerin, hydrogenated palm oil glyceride, light liquid paraffin, polycarbophil, purified water, sodium hydroxide and sorbic acid. Single-use vaginal applicator of 1.45 g in cartons, boxes of 6 and 18. Store at room temperature (15 to 25°C). Avoid exposure to extreme heat or cold.
Contraindications
Progesterone vaginal gel should not be used in individuals with any of the following conditions: unexplained abnormal vaginal bleeding; liver dysfunction or disease; known or suspected malignancy of the breast or genital organs; known or suspected progesterone-dependent neoplasia; known sensitivity to the product (progesterone or any of the other ingredients); missed abortion; active thrombophlebitis or thromboembolic disorders, or a history of hormone-associated thrombophlebitis or thromboembolic disorder.
Warnings
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.
Treatment should be discontinued if the results of liver function tests become abnormal or if cholestatic jaundice appears.
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.
Adverse Effects
In a multiple-dose study in a total of 57 women with ovarian failure undergoing a donor oocyte transfer procedure, the most frequently reported treatment emergent adverse reactions (in decreasing order) were cramps (nonspecific) (16%), breast pain (14%), headache (12%), pain (7%), bloating (7%), nausea (7%) and vaginal discharge (7%).
An increase (7%) of drowsiness frequency has been reported in a study on regular IVF.
Overdose
There have been no reports of overdosage with progesterone vaginal gel. Acute overdosage is unlikely with this product due to the concentration-dependent, rate-limited absorption of progesterone by the vaginal epithelium and the controlled release characteristics of the formulation. In the case of overdosage, however, discontinue progesterone vaginal gel, treat the patient symptomatically, and institute supportive measures.
As with all prescription drugs, this medicine should be kept out of the reach of children.
Dosage
Reproduction failure and In Vitro Fertilization Treatment: Progesterone vaginal gel is given at a dose of 90 mg. One application of 90 mg (1.125 g 8% gel) should be taken intravaginally daily or twice daily. Most women will respond to 90 mg every day. However, some women may need 90 mg twice daily. If pregnancy occurs, treatment may continue for up to 10 to 12 weeks.
