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Crinone 4% and Crinone 8% (progesterone gel) PHYSICIAN INFORMATION For Vaginal Use Only Rx only Content Updated: June 2017 | Crinone [Allergan, Inc.] | BioPortfolio

12:38 EST 27th January 2019 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

Crinone(progesterone gel) is a bioadhesive vaginal gel containing micronized progesterone in an emulsion system, which is contained in single use, polypropylene 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, Crinone 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 CHOand a molecular weight of 314.5.

The structural formula is:

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

Each applicator delivers 1.125 grams of Crinone gel containing either 45 mg (4% gel) or 90 mg (8% gel) of progesterone in a base containing glycerin, light mineral oil, polycarbophil, carbomer homopolymer Type B, 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.

Absorption

Due to the sustained release properties of Crinone, 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. 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 1.

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.

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.

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
 t1/2 (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
t1/2 - elimination half-life
F - relative bioavailability
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

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 to 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 "in-phase" 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 ß-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 )

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.

Assisted Reproductive Technology

Crinone 8% is indicated for progesterone supplementation or replacement as part of an Assisted Reproductive Technology ("ART") treatment for infertile women with progesterone deficiency.

Secondary Amenorrhea

Crinone 4% is indicated for the treatment of secondary amenorrhea. Crinone 8% is indicated for use in women who have failed to respond to treatment with Crinone 4%.

Crinone 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 Crinone 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 Crinone.

Nonclinical toxicity studies to determine the potential of Crinone to cause carcinogenicity or mutagenicity have not been performed. The effect of Crinone on fertility has not been evaluated in animals.

[See CLINICAL STUDIES , Assisted Reproductive Technology ]

Crinone 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 Crinone-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), Crinone 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 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. 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 Crinone 8% twice daily, treatment-emergent adverse events occurring in 5% or more of the women are shown in Table 3.

In a second clinical study of 139 women using Crinone 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.

Secondary Amenorrhea

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

TABLE 3 Treatment-Emergent Adverse Events in ≥ 5% of Women Receiving Crinone 8% Twice Daily Study COL1620-007US (n = 61)
 Body as a Whole
       Bloating  7%
       Cramps NOS  15%
       Pain  8%
 Central and Peripheral Nervous System
       Dizziness  5%
       Headache  13%
 Gastro-Intestinal System
       Nausea  7%
 Reproductive, Female
       Breast Pain  13%
       Moniliasis Genital  5%
       Vaginal Discharge  7%
 Skin and Appendages
       Pruritus Genital  5%
TABLE 4 Treatment-Emergent Adverse Events in ≥ 5% of Women Receiving Crinone 8% Once Daily Study COL1620-F01 (n = 139)
 Body as a Whole
       Abdominal Pain  12%
       Perineal Pain Female  17%
 Central and Peripheral Nervous System
       Headache  17%
 Gastro-Intestinal System
       Constipation  27%
       Diarrhea  8%
       Nausea  22%
       Vomiting  5%
 Musculo-Skeletal System
       Arthralgia  8%
 Psychiatric
       Depression  11%
       Libido Decreased  10%
       Nervousness  16%
       Somnolence  27%
 Reproductive, Female
       Breast Enlargement  40%
       Dyspareunia  6%
 Urinary System
       Nocturia  13%
TABLE 5 Treatment-Emergent Adverse Events in ≥ 5% of Women Receiving Estrogen Treatment and Crinone Every Other Day Studies COL1620-004US, COL1620-005US, COL1620-009US
  Estrogen + Crinone 4%
n = 62 
Estrogen + Crinone 8%
n = 65 
Body as a Whole 
     Abdominal Pain   3 (5%)  6 (9%)
     Appetite Increased  3 (5%)  5 (8%)
     Bloating  8 (13%)  8 (12%)
     Cramps NOS 12 (19%)  17 (26%)
     Fatigue  13 (21%)  14 (22%)
 Central and Peripheral Nervous System
     Headache  12 (19%)  10 (15%)
 Gastro-Intestinal System
     Nausea  5 (8%)  4 (6%)
 Musculo-Skeletal System
     Back Pain  5 (8%)  2 (3%)
     Myalgia  5 (8%)  0 (0%)
 Psychiatric
     Depression 12 (19%) 10 (15%)
     Emotional Lability 14 (23%)  14 (22%) 
     Sleep Disorder 11 (18%)  12 (18%)
 Reproductive, Female
     Vaginal Discharge  7 (11%) 2 (3%) 
 Resistance Mechanism
     Upper Respiratory Tract Infection  3 (5%) 5 (8%) 
 Skin and Appendages
     Pruritus Genital  1 (2%) 4 (6%) 

There have been no reports of overdosage with Crinone. In the case of overdosage, however, discontinue Crinone, treat the patient symptomatically, and institute supportive measures.

As with all prescription drugs, this medicine should be kept out of the reach of children.

Crinone 8% is administered vaginally at a dose of 90 mg once daily in women who require progesterone supplementation. Crinone 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 to 12 weeks.

Crinone 4% is administered vaginally every other day up to a total of six doses. For women who fail to respond, a trial of Crinone 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.

Crinone is available in the following strengths:

4% gel (45 mg) in a single use, disposable, white polypropylene vaginal applicator with a teal twist-off cap. Each applicator contains 1.3 g of gel and delivers 1.125 g of gel.

NDC 0023-6150-04 :  6 Single-use prefilled applicators.

8% gel (90 mg) in a single use, disposable, white polypropylene vaginal applicator with a teal twist-off cap. Each applicator contains 1.3 g of gel and delivers 1.125 g of gel.

NDC 0023-6151-08 : 15 Single-use prefilled applicators. Each applicator is wrapped and sealed in a foil overwrap. Store at 20-25ºC (68-77ºF). [See USP controlled room temperature.]

Keep out of reach of children. Rx only

For all medical inquiries contact:

Allergan USA, Inc.Irvine, CA 92612

1-800-678-1605

Distributed by: Allergan USA, Inc.Irvine, CA 92612

Content Updated: June 2017 202084-01

PATIENT INFORMATION

Crinone 4% and Crinone 8% (progesterone gel)For Vaginal Use Only Please read this information carefully before you start to use Crinone 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 healthcare provider.

What is Crinone?

Crinone is medicine that contains the female hormone called progesterone.

What is Crinone used for?

Who should not use Crinone? Do not start using Crinone if you:

What are the possible side effects of Crinone? Serious side effects include:

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

Common side effects include:

These are not all the possible side effects of Crinone. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

 

How should I use Crinone?

Use as directed by your healthcare provider.

Read the Instructions for Use included in this leaflet for information on the right way to use Crinone.

Additional information about Crinone

General information about the safe and effective use of Crinone

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use Crinone for another condition. Your doctor has prescribed this drug for you and you alone. Do not give this drug to anyone else, even if they have the same condition.

Keep Crinone out of the reach of children

This leaflet provides the most important information about Crinone. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Crinone that is written for health professionals.

You can get more information by calling the toll free number 1-888-776-4358 or visit www.crinoneusa.com .

What are the ingredients in Crinone?

Crinone contains either 45 mg (4% gel) or 90 mg (8% gel) of progesterone in a base containing glycerin, light mineral oil, polycarbophil, carbomer homopolymer Type B, hydrogenated palm oil glyceride, sorbic acid, purified water and may contain sodium hydroxide.

How should I store Crinone?

Store Crinone at room temperature between 68°F to 77°F (20°C to 25°C). Do not use Crinone after the expiration date printed on the box. INSTRUCTIONS FOR USE Crinone 4% and Crinone 8% ("KRI-noan")(progesterone gel)

For Vaginal Use Only

You will need the following supplies: See Figure A.

Step 1.  Remove the applicator from the sealed wrapper.

Step 2. Insert the plunger into the open end of the applicator. See Figure C. 

Step 3. Remove the cap. See Figures D and E.

Step 4. Prepare to insert the applicator. See Figure F. Choose the position that is most comfortable for you. For example, lying down on your back with your knees bent.

Step 5. Insert the applicator. See Figure G.

Step 6. Push the plunger. See Figure H.

Step 7. Remove the applicator from your vagina and throw it away in your household trash.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Rx only

For all medical inquiries contact:Allergan USA, Inc.

Irvine, CA 926121-800-678-1605

Distributed by: Allergan USA, Inc.

Irvine, CA 92612

Content Updated: June 2017

202084-01








Crinone (progesterone gel) 4%6 Single-Use Prefilled ApplicatorsNDC 0023-6150-04

Crinone(progesterone gel) 8%15 Single-Use Prefilled ApplicatorsNDC 0023-6151-08

Manufacturer

Allergan, Inc.

Active Ingredients

Source

Drugs and Medications [2 Associated Drugs and Medications listed on BioPortfolio]

Crinone [columbia laboratories, inc.]

Crinone® 4% Crinone® 8% (progesterone gel)

Crinone [actavis pharma, inc.]

Crinone 4% and Crinone 8%(progesterone gel)PHYSICIAN INFORMATIONFor Vaginal Use OnlyRx onlyContent Updated: August 2014

Clinical Trials [13 Associated Clinical Trials listed on BioPortfolio]

Compare the Difference of P4 Concentration in Serum and Endometrium After Vaginal and IM P Administration

Crinone is a micronized progesterone gel which is administrated via vaginal route and targeted drug delivery to uterine (first uterine pass effect) with lower serum concentration. This stu...

Efficacy and Safety of Crinone Versus Combination Medication

The study to compare to the efficacy and safety of Crinone versus combination medication in infertile women receive frozen-thawed embryo transfer (FET) in artificial cycles (AC).

Comparison of Crinone 8% Intravaginal Gel and IM Progesterone Supplementation for In Vitro Fertilization (IVF)

The goal of this research study is to compare the pregnancy rates for two different types of progesterone supplementation after in-vitro fertilization (IVF).

A Prospective Randomized Multicentre Study to Compare Crinone 8% Once Daily Versus Other Vaginal Progesterone.

To compare the effect of Crinone 8% administered once daily versus other vaginal progesterone in terms of ongoing pregnancy rate 5 weeks after embryo transfer as well as patient convenienc...

A Study Using Micronised Progesterone (Crinone® 8%) in the Luteal Phase Support of Women Undergoing in Vitro Fertilisation (IVF) and Embryo Transfer (ET)

This was an open-label, randomized, comparative, phase III study to evaluate the safety and efficacy of Crinone 8% in comparison with progesterone 60 mg intramuscular (i.m.) administered o...

PubMed Articles [0 Results]

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