Consumer medicine information

Crinone

Progesterone

BRAND INFORMATION

Brand name

Crinone

Active ingredient

Progesterone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Crinone.

What is in this leaflet

This leaflet answers some common questions about CRINONE. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using CRINONE against the benefits this medicine is expected to have for you.

If you have any questions about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What CRINONE is used for

CRINONE is a vaginal gel that contains natural progesterone.

Progesterone is a hormone that is produced by the ovaries during the second half of the menstrual cycle.

It is an essential hormone for preparing the uterus (womb) for pregnancy and on-going support of pregnancy.

The lack of normal progesterone production by the ovaries in the second half of the menstrual cycle is called luteal phase defect. Women who have this defect may have difficulties in becoming pregnant and may have a higher risk of miscarriage.

CRINONE is used to supplement progesterone in women who have luteal phase defect. CRINONE is also used to supplement or replace your own natural progesterone in Assisted Reproductive Technology procedures (e.g. IVF).

Your doctor may have prescribed CRINONE for another purpose.

Ask your doctor if you have any questions why CRINONE has been prescribed for you.

This medicine is available only with a doctor's prescription.

CRINONE is not addictive.

Before you use CRINONE

When you must not use it:

Do not use CRINONE if:

  • you have ever had an allergic reaction to progesterone or to any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • rash (itching or hives) on the skin
  • swelling of the face, lips, tongue or other parts of the body
  • shortness of breath, wheezing or troubled breathing or a tight feeling in your chest

Do not use CRINONE if you have, or have had any of the following conditions:

  • cancer of the breast and genital organs
  • porphyria
  • you have abnormal vaginal bleeding that has not been diagnosed, or is due to a recent or current missed abortion or miscarriage
  • you have or have ever had blood clots or a stroke
  • you have liver disease or abnormal laboratory results

Do not use CRINONE if you are breastfeeding.

Do not use CRINONE after the expiry date printed on the label of the pre-filled applicator and the carton. If you are taking this medicine after the expiry date has passed, it may not work.

Do not use CRINONE if the packaging is torn or shows signs of tampering.

Do not use CRINONE if the product appears to be discoloured, or the product does not look quite right.

If it has expired or is damaged, return it to your pharmacist or doctor for disposal.

If you are not sure whether you should start using CRINONE, talk to your doctor or pharmacist.

If you have not told your doctor about any of the above, tell them before you start using CRINONE.

CRINONE is not for use in children.

Do not use CRINONE to treat other complaints unless your doctor says it is safe.

Do not give this medicine to anyone else.

Before you use it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes

See your doctor for a check-up before you start to use CRINONE. The check-up should include a Pap smear, pelvic examination and breast examination.

You must tell your doctor or pharmacist if:

  • you are breast feeding
  • you are or have been very depressed
  • you are using other vaginal medications
  • you suffer from migraines, epilepsy or asthma
  • you suffer from heart, kidney or liver disease

If in doubt, consult your doctor or pharmacist before using CRINONE.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

CRINONE should not be used at the same time as other vaginal preparations.

If you forget to use it

If you forget a dose of CRINONE, use it as soon as you remember, and then continue on the same schedule as before.

Do not use more than the recommended daily dose.

If you use too much (overdose)

Immediately contact your doctor or the Poisons Information Centre (in Australia telephone 131 126, in New Zealand telephone 0800 764 766) if you are concerned that you have used too much CRINONE.

While you are using CRINONE

Things you must do:

Be sure to keep all your doctor's appointments so your progress can be checked.

Tell any other doctors or pharmacists you visit that you are using CRINONE.

If you are about to start taking any new medicines, tell the doctor or pharmacist that you are using CRINONE.

Things you must not do:

Do not give this medicine to anyone else; it may harm them even if the reasons for using it seem to be the same as yours.

Things to be careful of:

Be careful driving or operating machinery until you know how CRINONE affects you. Some people feel drowsy and sleepy when using CRINONE.

If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using CRINONE.

CRINONE helps most women with a lack of progesterone, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Tell your doctor if you notice any of the following side effects when using CRINONE:

Very common side effects

  • cramps, abdominal pain, perineal pain (around the genitals & the back passage)
  • headache
  • breast enlargement or breast pain
  • feelings of severe sadness and unworthiness, decreased sexual drive, sleepiness, feeling emotional
  • constipation, nausea
  • passing urine at night

Common side effects

  • bloating, pain
  • dizziness
  • vaginal discharge, itching of the vaginal area, vaginal thrush
  • diarrhoea, vomiting
  • painful sexual intercourse
  • painful joints

Other side effects may include vaginal spotting, vaginal irritation, mild application site reactions and hypersensitivity reactions manifesting as skin rash.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you do not understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

After using CRINONE

Storage

Keep this medicine where young children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep CRINONE in a cool place where it stays below 25°C and is not exposed to extreme heat or cold.

Do not store it, or any other medicine, in a bathroom or near a sink.

Do not leave it in the car. Heat and dampness can destroy some medicines.

Each applicator must be used once only. Use a new applicator for each treatment.

Disposal

If your doctor tells you to stop using CRINONE, or the gel has passed its expiry date, ask the pharmacist what to do with any leftover drug.

Product description

What it looks like

CRINONE is a soft, white to off-white gel. It is supplied in an applicator with a twist-off top. The applicator contains a plastic ball. Each applicator is sealed in a wrapper and contains a single dose of CRINONE.

Each applicator contains 1.45 g of gel and delivers a constant dose of 1.125 g of CRINONE gel containing 90 mg (8% gel) of progesterone.

CRINONE is available in boxes containing 6, 15 or 18 applicators*.

* Not all pack sizes may be available.

Ingredients

Active ingredients:

Progesterone

Other ingredients:

Hydrogenated palm glycerides,
Glycerol,
Carbomer 974P,
Sorbic acid,
Polycarbophil,
Sodium hydroxide,
Purified water,
Light liquid paraffin.

Australian Registration number

AUST R 83166

Supplier

CRINONE is supplied in Australia by:

Merck Healthcare Pty Ltd
Suite 1, Level 1, Building B
11 Talavera Road
Macquarie Park NSW 2113
E-mail: [email protected]
Phone: 1800 633 463

CRINONE is supplied in New Zealand by:

Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks
Auckland
E-mail: [email protected]
Phone: 0800 426 252

This leaflet was prepared in March 2020.

How to use CRINONE

CRINONE is applied directly from the applicator deep into the vagina. The applicator is designed to deliver a pre-measured dose of progesterone gel. A small amount of gel will be left in the applicator after usage. Do not be concerned because you will still be receiving the required dose.

How much to use and how often to use it

The amount of CRINONE used depends on the condition being treated.

Your doctor may prescribe one applicator of CRINONE either daily or twice daily and will advise you when to start treatment. If pregnancy occurs treatment may continue for up to 12 weeks or as directed by your doctor.

CRINONE should be used at the same time each day. If used twice a day, one applicator of CRINONE should be used in the morning and the other at night.

How to use CRINONE

Follow these steps carefully or as instructed by your doctor:

  1. Wash your hands well with soap and water.
  2. Remove the applicator from the sealed wrapper.
  3. DO NOT REMOVE THE TWIST-OFF TAB AT THIS TIME.
  4. Hold the applicator by the thick end. Shake down several times like a thermometer to ensure that the contents are at the thin end.
  5. The plastic ball in the thin end helps the gel to move down to the tip of the applicator. The ball also helps to control the release of the gel. The applicator is designed so that the ball cannot exit it.

  1. Hold the applicator by the flat section of the thick end. Twist off the tab at the thin end of the applicator and discard it.
DO NOT squeeze the thick end while twisting off the tab. This may release gel.

  1. Carefully insert the applicator into the vagina while you are in a sitting position or when lying on your back with the knees bent. Gently insert the thin end of the applicator well into the vagina.
  2. Squeeze the thick end of the applicator firmly to push the gel into the vagina. Remove the applicator and discard into a waste container. There may be some gel left in the applicator. Do not worry; you will still be receiving the correct dose.

CRINONE coats the vaginal lining to provide long-lasting release of progesterone.

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Crinone

Active ingredient

Progesterone

Schedule

S4

 

1 Name of Medicine

Progesterone.

6.7 Physicochemical Properties

Crinone (progesterone gel) is a bioadhesive vaginal gel which contains micronised progesterone in a diluted emulsion system, which is contained in single use, one piece polyethylene vaginal applicators.
Crinone is administered vaginally from a pre-filled applicator and is designed to provide a prolonged release of a natural progesterone into the vagina from a polycarbophil based gel.
The delivery system of Crinone is based on a vaginal moisturising formulation and provides sustained topical application of progesterone into the vagina. The Crinone delivery system is an emulsion that consists of lipophilic (lipid) and hydrophilic (aqueous) phases. The aqueous phase contains polycarbophil, a polymer that swells in the presence of water. Overall, it has a slightly negative ionic charge which produces temporary adhesion to the cell surface of the vaginal epithelium. The majority of progesterone is suspended and stored in the lipid phase while a small portion is dissolved in the aqueous phase. Absorption of progesterone occurs from the aqueous phase, which is then replenished from the lipid phase that acts as a reservoir.

Chemical structure.


Natural progesterone is a hormone secreted by the corpus luteum. Progesterone is the prototype of the hormone class known as progestogens. It is chemically described as pregn-4-ene-3, 20-dione and is practically insoluble in water and soluble in most organic solvents including alcohol. Progesterone has the following chemical structure:
Chemical formula: C21H30O2. Molecular weight: 314.5. Melting range: 127-131°C.

CAS number.

57-83-0.

2 Qualitative and Quantitative Composition

Each applicator contains 1.45 g of gel and delivers a constant dose of 1.125 g of Crinone gel containing 90 mg (8% gel) of progesterone.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Prolonged release vaginal gel with polyethylene applicator. Crinone vaginal gel has the appearance of a soft, white to off white gel.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta and adrenal gland. In the presence of adequate oestrogen, 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 exogenous oestrogen and progesterone have been noted in functionally agonadal women through the sixth decade of life. Progesterone administration decreases the circulatory levels of gonadotropins.

Clinical trials.

In clinical studies of patients (n=99) with either partial or premature ovarian failure who were candidates to receive a donor oocyte transfer as an Assisted Reproductive Technology (ART) procedure were randomised to receive either Crinone twice daily or intramuscular progesterone 100 mg daily. The study was divided into three phases. 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 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 as part of the Pilot Cycle to determine their endometrial response. Of the 55 evaluable endometrial biopsies in the Crinone 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 and had an 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), occurred in 26 women (48%). In these 54 women, 17 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, Crinone was used in luteal phase support of women with tubal or idiopathic infertility due to endometriosis and normal ovulatory cycles, undergoing in vitro fertilisation (IVF) procedures. All women received a GnRH (gonadotropin-releasing hormone) analog to suppress endogenous progesterone, human menopausal gonadotropin and human chorionic gonadotropin. In this multi-center, open labelled study 139 women (aged 22-38 years) received Crinone once daily beginning within 24 hours of embryo transfer and continuing through 30 days 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.
Use of Crinone for Pre-Menstrual Tension (PMT) and Hormone Replacement Therapy (HRT) is not supported by the information provided in this product label.

5.2 Pharmacokinetic Properties

Limited pharmacokinetic data are available for Crinone, however studies have been conducted and the pharmacokinetic parameters from these studies can be seen in Tables 1 and 2.

Absorption.

The bioavailability of progesterone in Crinone was determined relative to progesterone administered intramuscularly, orally and vaginally.
In one single dose parallel group study, 18 healthy, postmenopausal women received single doses of either 90 mg progesterone vaginally in Crinone 8% or, 100 mg progesterone orally in a capsule, or 100 mg progesterone vaginally in a capsule. The pharmacokinetic parameters are shown in Table 1.
In a further study, comprised two crossover comparisons of progesterone pharmacokinetics in 20 healthy postmenopausal women, 10 of the subjects received a dose of 45 mg, on two different occasions; once as intravaginal gel (Crinone 4%) and on the other as an intramuscular injection (IMI). The other 10 subjects received a dose of 90 mg by each route. The pharmacokinetic parameters are shown in Table 2.
These pharmacokinetic parameters show that for the 45 mg and 90 mg dose the gel is 28% and 20% bioavailable in comparison with the IMI route, respectively.

Distribution.

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

Metabolism.

The major urinary metabolite of 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-pregnenolone) and 5α-pregnan-3α-ol- 20-one (5α-pregnenolone) which may be associated with sedation and hypnosis.

Excretion.

Progesterone undergoes both biliary and renal elimination. Following an injection of labelled progesterone, 50-60% of the excretion of progesterone metabolites occurs via the kidneys and approximately 10% via the bile and faeces. Overall recovery of labelled material accounts for 70% of an administered dose, with the remainder of the dose not characterised with respect to elimination. Only a small portion of unchanged progesterone is excreted in the bile.

5.3 Preclinical Safety Data

The effect of Crinone on fertility has not been evaluated in animals.

Genotoxicity.

No studies to determine the genotoxic potential of Crinone have been performed.

Carcinogenicity.

No studies to determine the carcinogenic potential of Crinone have been performed. Progesterone has been shown to induce and/or promote mammary, uterine, ovarian, endometrial, cervical and vaginal tumours in experimental animals. The clinical relevance of these findings is unknown.

4 Clinical Particulars

4.1 Therapeutic Indications

Crinone is used in IVF and ART, where luteal phase support is indicated.

4.3 Contraindications

1. Known or suspected malignancy of the breast or genital organs.
2. Missed abortion.
3. Undiagnosed uterine bleeding.
4. Liver dysfunction or disease.
5. Known hypersensitivity to any of the components of the Crinone formulation.
6. Known or suspected progesterone dependent neoplasia.
7. Active thrombophlebitis or thromboembolic disorders, cerebral apoplexy, or a history of hormone associated thrombophlebitis or thromboembolic disorders.
8. Acute porphyria.

4.4 Special Warnings and Precautions for Use

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.
The pre-treatment physical examination should include particular attention to the breasts and pelvic organs, and a Papanicolaou smear should be obtained.
As progestogens may cause some degree of fluid retention, a woman who has any condition that might be influenced by this factor (such as epilepsy, asthma, migraine, and cardiac or renal dysfunction) requires careful observation.
In cases of breakthrough bleeding, as with all cases of irregular vaginal bleeding, diagnostic measures may be indicated to assess whether organic disease is present.
Patients with a history of depression should be carefully observed and Crinone discontinued if the depression recurs to a serious degree.
Progestogens may worsen the manifestations of pre-existing porphyria. Therefore the use of Crinone in such patients is not recommended.
The pathologist should be advised of progestogen therapy when relevant specimens are submitted because of the influence of progestogens on the structure and pathology of organs such as the endometrium.
Crinone should not be used concurrently with other vaginal therapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

No data available.

Paediatric use.

Crinone should not be used in children.

Effects on laboratory tests.

There is no evidence that Crinone has any effects on laboratory tests other than endometrial histology tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Although no interactions with other drugs have been reported, Crinone is not recommended for use concurrently with other vaginal preparations.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 4.1 Therapeutic Indications.
(Category A)
Crinone has been used to successfully support embryo implantation and maintain pregnancies through its use as part of ART treatment regimens.
Do not use during lactation. Detectable amounts of progestogens have been identified in the milk of mothers receiving them. The effect of this on the nursing infant has not been determined.

4.8 Adverse Effects (Undesirable Effects)

In a study of 63 women with ovarian failure undergoing a donor oocyte transfer procedure receiving Crinone twice daily, treatment-emergent adverse events occurring in ≥ 5% of the women is shown below.

Note.

Very common: greater than or equal to 10%.
Common: greater than or equal to 1% and < 10%.

Body as a whole.

Very common: cramps.
Common: bloating, pain.

Central and peripheral nervous system.

Very common: headache.
Common: dizziness.

Gastro-intestinal.

Common: nausea.

Reproductive, female.

Very common: breast pain.
Common: genital moniliasis, vaginal discharge.

Skin and appendages.

Common: genital pruritus.
In the second study of 139 women using Crinone once daily for luteal support while undergoing IVF procedure, treatment-emergent adverse events reported in ≥ 5% of women are shown below.

Body as a whole.

Very common: abdominal pain, perineal pain.

Central and peripheral nervous system.

Very common: headache.

Gastro-intestinal.

Very common: constipation, nausea.
Common: diarrhoea, vomiting.

Reproductive, female.

Very common: breast enlargement.
Common: dyspareunia.

Musculo-skeletal.

Common: arthralgia.

Psychiatric.

Very common: depression, decreased libido, nervousness and somnolence.

Urinary system.

Very common: nocturia.
In addition, intermenstrual bleeding (spotting), vaginal irritation and other mild application site reactions, as well as hypersensitivity reactions usually manifesting as skin rash, have been reported post-marketing. For adverse reactions identified during post-marketing surveillance, quantification of frequency has not been attempted, but most likely uncommon to very rare.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems in Australia, or at https://nzphvc.otago.ac.nz/reporting/ in New Zealand.

4.2 Dose and Method of Administration

Reproductive failure and in vitro fertilisation treatment.

Crinone is given at a dose of 90 mg. Crinone treatment is started within 4 days, preferably 2 days, after hCG (human chorionic gonadotropin) administration. One application of 90 mg (1.125 g, 8% gel) should be given vaginally daily or twice daily. Most women will respond to 90 mg given daily. However, some women may need 90 mg twice daily. If pregnancy occurs treatment may continue for up to 10 to 12 weeks.

Instructions for use/ handling.

Crinone is administered vaginally. Remove the applicator from the sealed wrapper.
Do not remove the twist-off cap at this stage.
1. Grip the applicator firmly by the thick end. Shake down like a thermometer to ensure that the contents are at the thin end.
2. Twist off the tab and discard.
3. The applicator may be inserted into the vagina while the patient is in a sitting position or when lying on their back with knees bent. Gently insert the thin end of applicator well into the vagina.
4. Press the thick end of the applicator firmly to deposit gel. Remove the applicator and discard in a waste container.
Crinone coats the vaginal mucosa to provide prolonged release of progesterone.

4.7 Effects on Ability to Drive and Use Machines

Drivers and users of machines are warned that risk of somnolence may occur. Special care should be taken if it is essential that patients drive or operate machinery while undergoing treatment with Crinone.

4.9 Overdose

There have been no reports of overdosage with Crinone. Acute overdosage is unlikely with this product due to the concentration-dependent, rate-limited absorption of progesterone by the vaginal epithelium and the prolonged release characteristics of the formulation. However, in case of overdosage, discontinue Crinone and treat the patient symptomatically.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia) or 0800 764 766 (New Zealand).

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

6 Pharmaceutical Particulars

6.1 List of Excipients

Glycerol, light liquid paraffin, hydrogenated palm glycerides, carbomer 974P, polycarbophil, sorbic acid, sodium hydroxide and purified water.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

Information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG) in Australia or on Medsafe Product Detail in New Zealand. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

The product must be stored below 25°C.

6.5 Nature and Contents of Container

Crinone is supplied as single use, one piece, disposable, white polyethylene vaginal applicators with a twist off top in packs of 6, 15 and 18*.
Each applicator is individually wrapped and sealed in a foil over wrap.
* Not all pack sizes may be available.

6.6 Special Precautions for Disposal

Any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes