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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.
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 C 21 H 30 O 2 and a molecular weight of 314.5. The structural formula is:
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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.
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.
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.
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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.
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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 5(beta)-pregnan-3(alpha), 20(alpha)-diol glucuronide which is present in plasma in the conjugated form only. Plasma metabolites also include 5(beta)-pregnan-3(alpha)-ol-20-one (5(beta)-pregnanolone) and 5(alpha)-pregnan-3(alpha)-ol-20-one (5(alpha)-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.
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 recieve 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 (beta)-hCG levels) occurred in 26 women (48%). In these 26 women, 17 women (65%) delivered a total of 25 newborns, seven women (27%) had spontaneous abortions and two women (8%) 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 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.
Prochieve® 8% is indicated for progesterone supplementation or replacement as part of an Assisted Reproductive Technology ("ART") treatment for infertile women with progesterone deficiency.
Prochieve® 4% is indicated for the treatment of secondary amenorrhea. Prochieve® 8% is indicated for use in women who have failed to respond to treatment with Prochieve® 4%.
Prochieve® should not be used in individuals with any of the following conditions:
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.
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 Prochieve® administration. Small, white globules may appear as a vaginal discharge possibly due to gel accumulation, even several days after usage.
No drug interactions have been assessed with Prochieve®.
Nonclinical toxicity studies to determine the potential of Prochieve® to cause carcinogenicity or mutagenicity have not been performed. The effect of Prochieve® on fertility has not been evaluated in animals.
Pregnancy (See CLINICAL PHARMACOLOGY , subsection Clinical Studies )
Prochieve® 8% has been used to support embryo implantation and maintain pregnancies through its use as part of ART treatment regimens in two clinical studies (studies COL1620-007US and COL1620-F01). In the first study (COL1620-007US), 54 Prochieve®-treated women had donor oocyte transfer procedures, and clinical pregnancies occurred in 26 women (48%). The outcomes of these 26 pregnancies were as follows: one woman had an elective termination of pregnancy at 19 weeks due to congenital malformations (omphalocele) associated with a chromosomal abnormality; one woman pregnant with triplets had an elective termination of her pregnancy; seven women had spontaneous abortions; and 17 women delivered 25 apparently normal newborns.
In the second study (COL1620-F01), Prochieve® 8% was used in the luteal phase support of women undergoing in vitro fertilization ("IVF") procedures. In this multi-center, open-label study, 139 women 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. Of the 47 newborns delivered, one had a teratoma associated with a cleft palate; one had respiratory distress syndrome; 44 were apparently normal and one was lost to follow-up.
The safety and effectiveness in geriatric patients (over age 65) have not been established.
Safety and effectiveness in pediatric patients have not been established.
Detectable amounts of progestins have been identified in the milk of mothers receiving them. The effect of this on the nursing infant has not been determined.
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.
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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.
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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.
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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
Platelet, Bleeding Clotting --purpura
Psychiatric --aggressive reactions, forgetfulness, insomnia
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
There have been no reports of overdosage with Prochieve®. In the case of overdosage, however, discontinue Prochieve®, treat the patient symptomatically, and institute supportive measures.
As with all prescription drugs, this medicine should be kept out of the reach of children.
Prochieve® 8% is administered vaginally at a dose of 90 mg once daily in women who require progesterone supplementation. Prochieve® 8% is administered vaginally at a dose of 90 mg twice daily in women with partial or complete ovarian failure who require progesterone replacement. If pregnancy occurs, treatment may be continued until placental autonomy is achieved, up to 10-12 weeks.
Prochieve® 4% is administered vaginally every other day up to a total of six doses. For women who fail to respond, a trial of Prochieve® 8% every other day up to a total of six doses may be instituted.
It is important to note that a dosage increase from the 4% gel can only be accomplished by using the 8% gel. Increasing the volume of gel administered does not increase the amount of progesterone absorbed.
SEE Prochieve® PATIENT INFORMATION SHEET - HOW TO USE Prochieve®. Note: The PATIENT INFORMATION SHEET contains special instructions for using the applicator at altitudes above 2500 feet in order to avoid a partial release of Prochieve® before vaginal insertion.
Prochieve® is available in the following strengths:
4% gel (45 mg) in a single use, one piece, disposable, white polyethylene vaginal applicator with a twist-off top. Each applicator contains 1.45 g of gel and delivers 1.125 g of gel.
NDC-55056-0406-1 - 6 Single-use prefilled applicators.
8% gel (90 mg) in a single use, one piece, disposable, white polyethylene vaginal applicator with a twist-off top. Each applicator contains 1.45 g of gel and delivers 1.125 g of gel.
NDC-55056-0806-1 - 6 Single-use prefilled applicators.
NDC-55056-0818-1 - 18 Single-use prefilled applicators
Each applicator is wrapped and sealed in a foil overwrap.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
Rx only.
Manufactured for: Columbia Laboratories, Inc. Livingston, NJ 07039
Manufactured by: Fleet Laboratories Ltd., Watford, United Kingdom
40905010004 Revised November 2004
Prochieve® 8%
(progesterone gel)
For Vaginal Use Only
FOR PROGESTERONE SUPPLEMENTATION OR REPLACEMENT AS PART OF AN ASSISTED REPRODUCTIVE TECHNOLOGY ("ART") TREATMENT FOR INFERTILE WOMEN WITH PROGESTERONE DEFICIENCY
Please read this information carefully before you start to use Prochieve® and each time your prescription is renewed, in case anything has changed. This leaflet does not take the place of discussions with your doctor. If you still have any questions, ask your doctor or health-care provider.
What Prochieve® is
Prochieve® is a specially formulated gel that you insert in your vagina. It contains the natural female hormone called progesterone. Prochieve® 8% is used as part of a program for women who are undergoing fertility treatment.
Understanding the role of Prochieve® in your infertility treatment
Progesterone is one of the hormones essential for maintaining a pregnancy. If you are undergoing ART treatment and your doctor has determined your body does not produce enough progesterone on its own, Prochieve® may be prescribed to provide the progesterone you need.
The progesterone in Prochieve® will help prepare the lining of your uterus so that it is ready to receive and nourish a fertilized egg. If pregnancy occurs, Prochieve® may be supplemented for 10-12 weeks until production of progesterone by the placenta is adequate.
When you should not use Prochieve®
Risks of Prochieve®
Be alert for unusual signs and symptoms. If any of these warning signals (or any other unusual symptoms) happen while you are using Prochieve®, call your doctor immediately:
You should also notify your doctor if you experience depression, worsening of your diabetic condition, or fluid retention.
Possible side effects of Prochieve®
In addition to the risks listed above, the following side effects have been reported with Prochieve® used either for progesterone supplementation or for replacement as part of an ART treatment for infertile women with progesterone deficiency. Consult your doctor if you experience any of the side effects mentioned below, or other side effects.
SIDE EFFECTS REPORTED AT A FREQUENCY OF 5% OR GREATER
SIDE EFFECTS REPORTED AT A FREQUENCY RANGING FROM 1% TO 5%
SIDE EFFECTS REPORTED AT A FREQUENCY OF LESS THAN 1%
*If you experience dizziness or sleepiness, do not drive or operate machinery.
How Prochieve® works
Prochieve® has been formulated to be administered through the vagina. The moisturizing gel in Prochieve® forms a coating on the walls of the vagina which allows for absorption of progesterone through the vaginal tissue. Small, white globules may appear as a vaginal discharge possibly due to gel accumulation, even several days after usage. Prochieve® contains no irritating perfumes or dyes.
Other information
How to use Prochieve®
The dosage is one application of the 8% gel (90 mg of progesterone) vaginally, daily or twice daily as directed by your doctor. If you become pregnant, your doctor may decide to continue treatment for up to 10 to 12 weeks.
Prochieve® is to be applied directly from the specially designed sealed applicator into the vagina. The applicator is designed to deliver a premeasured dose of Prochieve®. A small amount of gel will be left in the tube after usage. Do not be concerned because you will still be receiving the appropriate, measured dosage.
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SPECIAL INSTRUCTIONS FOR USE AT ALTITUDES ABOVE 2500 FEET
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Prochieve® coats the vaginal lining to provide long-lasting release of progesterone. Small, white globules may appear as a vaginal discharge possibly due to gel accumulation, even several days after usage. It is not unusual, but if you are concerned, discuss this with your doctor.
If you forget a dose of Prochieve®, use it as soon as you remember, but do not use more than the recommended daily dose. Prochieve® should not be used at the same time that you are using other vaginal therapy.
This leaflet provides the most important information about Prochieve®. If you want to read more, ask your doctor or pharmacist about the professional leaflet. You may need their help to understand some of the information.
Prochieve® is available as 8% gel (90 mg of progesterone).
Each box of the 8% gel contains either six or eighteen single use, disposable vaginal applicators with a twist-off tab. Each applicator is wrapped and sealed in a foil overwrap.
Prochieve® should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
Do not use Prochieve® after the expiration date which is printed on the box.
Manufactured for: Columbia Laboratories, Inc., Livingston, NJ 07039
Manufactured by: Fleet Laboratories Ltd., Watford, United Kingdom
40905010004 Revised November 2004
Prochieve® 4% and
Prochieve® 8%
(progesterone gel)
For Vaginal Use Only
FOR THE TREATMENT OF SECONDARY AMENORRHEA (ABSENCE OF MENSES IN WOMEN WHO HAVE PREVIOUSLY HAD A MENSTRUAL PERIOD)
Please read this information carefully before you start to use Prochieve® and each time your prescription is renewed, in case anything has changed. This leaflet does not take the place of discussions with your doctor. If you still have any questions, ask your doctor or health-care provider.
What Prochieve® is
Prochieve® is a specially formulated gel that you insert in your vagina. It contains the natural female hormone called progesterone. The 4% gel is used for women whose menstrual cycle has stopped. The 8% gel is to be used when the 4% gel has not worked.
Understanding the role of Prochieve® in the treatment of your menstrual irregularities
Progesterone is one of the hormones essential for regular menstrual periods. If your doctor has determined your body does not produce enough progesterone on its own, Prochieve® may be prescribed to provide the progesterone you need.
When you do not produce enough progesterone, menstrual irregularities can occur. Prochieve® can provide you with the progesterone needed during a normal menstrual cycle.
When you should not use Prochieve®
Risks of Prochieve®
Be alert for unusual signs and symptoms. If any of these warning signals (or any other unusual symptoms) ha-ppen while you are using Prochieve®, call your doctor immediately:
You should also notify your doctor if you experience depression, worsening of your diabetic condition, or fluid retention.
Possible side effects of Prochieve®
In addition to the risks listed above, the following side effects have been reported in studies with Prochieve® used for the treatment of menstrual irregularities due to progesterone deficiency. In these studies, women were treated with estrogen prior to and during Prochieve® therapy. All side effects reported at a frequency of 5% or greater after Prochieve® was added to estrogen therapy also were reported with estrogen therapy alone. Consult your doctor if you experience any of the side effects mentioned below, or other side effects.
SIDE EFFECTS REPORTED AT A FREQUENCY OF 5% OR GREATER
SIDE EFFECTS REPORTED AT A FREQUENCY RANGING FROM 1% TO 5%
SIDE EFFECTS REPORTED AT A FREQUENCY OF LESS THAN 1%
*If you experience dizziness or sleepiness, do not drive or operate machinery.
How Prochieve® works
Prochieve® has been formulated to be administered through the vagina. The moisturizing gel in Prochieve® forms a coating on the walls of the vagina which allows for absorption of progesterone through the vaginal tissue. Small, white globules may appear as a vaginal discharge possibly due to gel accumulation, even several days after usage. Prochieve® contains no irritating perfumes or dyes.
Other information
How to use Prochieve®
The dosage is one application of the 4% gel (45 mg of progesterone), vaginally, every other day as directed by your doctor, for a total of six doses. In some cases, your doctor may prescribe the 8% gel (90 mg of progesterone) every other day, for a total of six doses.
It is important to note that a dosage increase from the 4% gel can only be accomplished by using the 8% gel. Increasing the volume of gel administered does not increase the amount of progesterone absorbed.
Prochieve® is to be applied directly from the specially designed sealed applicator into the vagina. The applicator is designed to deliver a premeasured dose of Prochieve®. A small amount of gel will be left in the tube after usage. Do not be concerned because you will still be receiving the appropriate, measured dosage.
 |
 |
 |
 |
SPECIAL INSTRUCTIONS FOR USE AT ALTITUDES ABOVE 2500 FEET
 |
 |
Prochieve® coats the vaginal lining to provide long-lasting release of progesterone. Small, white globules may appear as a vaginal discharge possibly due to gel accumulation, even several days after usage. It is not unusual, but if you are concerned, discuss this with your doctor.
If you forget a dose of Prochieve®, use it as soon as you remember, but do not use more than the recommended daily dose. Prochieve® should not be used at the same time that you are using other vaginal therapy.
This leaflet provides the most important information about Prochieve®. If you want to read more, ask your doctor or pharmacist about the professional leaflet. You may need their help to understand some of the information.
Prochieve® is available in two strengths: 4% gel (45 mg of progesterone) and 8% gel (90 mg of progesterone).
Each box of the 4% gel contains six single use, disposable vaginal applicators with a twist-off tab. Each box of the 8% gel contains either six or eighteen single use, disposable vaginal applicators with a twistoff tab. Each applicator is wrapped and sealed in a foil overwrap.
Prochieve® should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
Do not use Prochieve® after the expiration date which is printed on the box.
Manufactured for: Columbia Laboratories, Inc., Livingston, NJ 07039
Manufactured by: Fleet Laboratories Ltd., Watford, United Kingdom
40905010004 Revised November 2004