Consumer medicine information

Utrogestan 200

Progesterone

BRAND INFORMATION

Brand name

Utrogestan 200

Active ingredient

Progesterone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Utrogestan 200.

SUMMARY CMI

UTROGESTAN 200®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using UTROGESTAN?

UTROGESTAN contains the active ingredient progesterone. UTROGESTAN is used for women who need extra progesterone while undergoing fertility treatment (e.g. ART); for the treatment of unexplained threatened miscarriage; for the prevention of preterm birth in women with a short cervix and or history of spontaneous preterm birth.

For more information, see Section 1. Why am I using UTROGESTAN? in the full CMI.

2. What should I know before I use UTROGESTAN?

Do not use if you have ever had an allergic reaction to UTROGESTAN or any of the ingredients listed at the end of the CMI. Do not use if you are breast-feeding.

Talk to your doctor if you have any other medical conditions or are taking any other medicines.

For more information, see Section 2. What should I know before I use UTROGESTAN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with UTROGESTAN and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use UTROGESTAN?

  • UTROGESTAN should be used as instructed by your doctor at the recommended dose and timeframes for each use.
    UTROGESTAN is intended to be inserted into the vagina.

More instructions can be found in Section 4. How do I use UTROGESTAN? in the full CMI.

5. What should I know while using UTROGESTAN?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using UTROGESTAN.
  • Follow all direction given to you by your doctor carefully.
Things you should not do
  • Do not use if you have unusual vaginal bleeding that has not been evaluated by your doctor,
  • Do not use if you have known missed abortions or ectopic pregnancy
  • Do not use if you have or are suspected of having cancer of the breast or genital tract
  • Do not use if you have a blood clot or bleeding on the brain.
  • Do not use if your liver is not working well.
Driving or using machines
  • Be careful driving or operating machinery until you know how UTROGESTAN affects you. Some people may experience drowsiness or dizziness.
  • Make sure you know how you react to UTROGESTAN before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive.
Drinking alcohol
  • Alcohol may increase the effect of UTROGESTAN
Looking after your medicine
  • Store below 30°C.
  • Do not refrigerate.

For more information, see Section 5. What should I know while using UTROGESTAN? in the full CMI.

6. Are there any side effects?

Call your doctor straight away if you experience swelling of the face, lips, mouth or throat which may cause difficulty swallowing or breathing or hives. Tell your doctor if you notice any of the following and they worry you: burning, local itching, and vaginal disorders. Systemic side effects of tiredness and dizziness observed with the oral form have not been reported at the recommended dosages for vaginal use.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

UTROGESTAN 200®

Active ingredient(s): Progesterone (micronised)


Consumer Medicine Information (CMI)

This leaflet provides important information about using UTROGESTAN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using UTROGESTAN.

Where to find information in this leaflet:

1. Why am I using UTROGESTAN?
2. What should I know before I use UTROGESTAN?
3. What if I am taking other medicines?
4. How do I use UTROGESTAN?
5. What should I know while using UTROGESTAN?
6. Are there any side effects?
7. Product details

1. Why am I using UTROGESTAN?

UTROGESTAN contains the active ingredient micronised progesterone. UTROGESTAN is provided as a soft capsule to be inserted deep into the vagina and contains the natural female hormone progesterone. Progesterone is a hormone essential for maintaining pregnancy.

UTROGESTAN is used for:

  • Women who need extra progesterone while undergoing fertility treatment (e.g. ART)
    If you are having fertility treatment and your doctor has determined your body does not produce enough progesterone your doctor may prescribed UTROGESTAN.
    The progesterone will help prepare your uterus (womb) to receive and maintain a fertilised egg.
    Once pregnancy occurs UTROGESTAN may be used until production of progesterone by the placenta is adequate.
  • Prevention of preterm birth in women with singleton pregnancy who have a short cervix (midtrimester sonographic cervix ≤ 25 mm) and/or a history of spontaneous preterm birth.
    There is limited evidence supporting the use of progesterone with twin/multiple pregnancies.
    There is insufficient evidence to recommend the use of progesterone in women with preterm labour or ‘other’ risk factors for preterm birth.
  • Reducing the risk of miscarriage in women with bleeding in the current pregnancy and a history of three or more previous miscarriages.
    The benefit of this medicine was shown to be limited to women who have had three or more previous miscarriages. However, your doctor may consider it appropriate to use in women with less than three miscarriages, who have a reduced chance of future pregnancy.
    Other known causes of potential miscarriage should be ruled out before starting treatment.

Your doctor may have prescribed UTROGESTAN for another purpose. Ask your doctor if you have any questions about why this medicine has been prescribed for you.

2. What should I know before I use UTROGESTAN?

Always check the ingredients to make sure you can use this medicine.

Do not use UTROGESTAN if:

  • you are allergic to progesterone, or any of the ingredients listed at the end of this leaflet.
  • you have or have had any of the following conditions:
    - Unusual vaginal bleeding that has not been evaluated by your doctors;
    - Known missed abortions or ectopic pregnancy;
    - Severe liver problems;
    - Known or suspected cancer of the breast or genital tract;
    - Blood clots (thrombophlebitis or thromboembolic disorder), such as inflammation of a vein, deep vein blood clotting (thrombosis) or a blood clot that travelled to the lungs (pulmonary embolism);
    - Bleeding on the brain;
    - Porphyria disorder (a blood disease).

Warnings

Check with your doctor if you:

  • have or have had any medical conditions, especially the following:
    - Epilepsy
    - Migraine
    - High blood pressure
    - Asthma
    - Heart, liver or kidney diseases
    - Diabetes
    - History of depression
  • Tell your doctor or pharmacist if you have allergies to:
    - Any other medicines
    - Soya (UTROGESTAN contains soya lecithin which may cause hypersensitivity reactions)
    - Any other substances, such as foods, preservatives or dyes

If you have not told your doctor or pharmacist about any of the above, tell them before you use UTROGESTAN.

  • If you think you have miscarried, you should speak to your doctor as you will need to stop using UTROGESTAN.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

UTROGESTAN is not suitable for use as a contraceptive.

Pregnancy and breastfeeding

During fertility treatment UTROGESTAN should only be used during the first three months of pregnancy, unless your doctor has recommended otherwise.

For treatment to reduce the risk of miscarriage in women with bleeding in the current pregnancy UTROGESTAN should be initiated at the first sign of vaginal bleeding during the first trimester and should continue at least until the 16th week of pregnancy.

For the prevention of preterm birth UTROGESTAN may be prescribed by your Doctor during the second trimester (16 – 24 weeks gestation) and should be continued to the end of the 36th week of your pregnancy or until delivery.

Do not use UTROGESTAN if you are breast-feeding.

Children and adolescents

Do not give UTROGESTAN to a child of any age. UTROGESTAN has not been evaluated in adolescents with childbearing potential.

3. What if I am taking other medicines?

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

Some medicines may interfere with UTROGESTAN and affect how it works or how these medicines work. These include:

  • Carbamazepine, Phenobarbital and Phenytoin (medicines for epilepsy)
  • Rifampicin
  • Phenylbutazone
  • Spironolactone
  • Griseofulvin
  • Some antibiotics including Ampicillins and Tetracyclines
  • Bromocriptine
  • Cyclosporin
  • Ketoconazole

These medicines may be affected by UTROGESTAN or may affect how well they work. You may need different amounts of your medicine or you may need to use different medicines. Your doctor or pharmacist will advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect UTROGESTAN.

4. How do I use UTROGESTAN?

How much to use

Your doctor will tell you how many capsules you need to use each day.

  • For supplementation during Assisted Reproductive Technology, the recommended dosage is 600 mg/day, in three divided doses from the day of embryo transfer until at least the 7th week of pregnancy and not later than the 12th week of pregnancy.
  • For treatment to reduce the risk of miscarriage in women with bleeding in the current pregnancy, the usual dose is 400 mg twice daily from the first sign of vaginal bleeding until at least the 16th week of pregnancy.
  • For the prevention of preterm birth the usual dose is 200 mg/day recommended at bedtime, during the second trimester (16-24 weeks gestation) and should be continued until the end of the 36th week of your pregnancy or until delivery.

When to take / use UTROGESTAN

  • UTROGESTAN is intended to be inserted into the vagina.
  • Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.
  • Do not stop using UTROGESTAN or lower the dosage without checking with your doctor.
  • UTROGESTAN should not be used at the same time as other vaginal preparations.

If you forget to use UTROGESTAN

UTROGESTAN should be used as instructed by your doctor for the recommended timeframes for each use.

If you miss a dose, use it as soon as you remember, and then go back to using your medicine as you would normally.

If it is almost time for your next dose, skip the dose you missed and go back to using your medicine when you are meant to.

Do not use a double dose to make up for the dose you missed.

If you use too much UTROGESTAN

If you think that you or anyone else may have used too much UTROGESTAN, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Symptoms of an overdose with UTROGESTAN include feeling dizzy or feeling tired.

5. What should I know while using UTROGESTAN?

UTROGESTAN contains soya lecithin. If you are allergic to soya do not use UTROGESTAN.

Things you should do

Call your doctor straight away if you:

  • Experience swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • Hives

You may have had a very serious reaction to UTROGESTAN and may need urgent medical attention or hospitalization.

Remind any doctor, dentist or pharmacist you visit that you are using UTROGESTAN.

Things you should not do

  • Do not stop using this medicine or lower the dosage without checking with your doctor or pharmacist.
  • UTROGESTAN should not be used at the same time as other vaginal preparations.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how UTROGESTAN affects you.

UTROGESTAN may cause drowsiness or dizziness in some people. Make sure you know how you react to UTROGESTAN before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs, do not drive.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may increase the effect of UTROGESTAN.

Looking after your medicine

Store below 30°C. Do not refrigerate.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Side effects such as:
  • Burning
  • Local itching
  • Vaginal disorders
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Side effects such as:
  • Swelling of the face, lips, mouth or throat which may cause difficulty swallowing or breathing.
  • Hives
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Systemic side effects of tiredness and dizziness observed with the oral form have not been reported at the recommended dosages for vaginal use.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription. This medicine is not addictive.

What UTROGESTAN contains

Active ingredient
(main ingredient)
Progesterone 200 mg
Other ingredients
(inactive ingredients)
Sunflower oil
Lecithin
Gelatin
Glycerol
Titanium dioxide
Purified water
Potential allergensLecithin (from soya)

Do not take this medicine if you are allergic to any of these ingredients.

What UTROGESTAN looks like

UTROGESTAN 200 is an ovoid, slightly yellow soft capsule, containing a whitish oily suspension.

UTROGESTAN 200 is supplied in blister strips packaged in an outer carton. Each carton contains 7 (trade or starter pack), 14, 15, 21, 28, 30, 42, 45, 56, 84 or 90* capsules.

* Not all pack sizes may be marketed

AUST R 232824

Who distributes UTROGESTAN

Besins Healthcare Australia Pty Ltd
Level 16, Tower 2, Darling Park,
201 Sussex Street,
Sydney NSW 2000

This leaflet was prepared in February 2022.

Published by MIMS April 2022

BRAND INFORMATION

Brand name

Utrogestan 200

Active ingredient

Progesterone

Schedule

S4

 

1 Name of Medicine

Progesterone.

2 Qualitative and Quantitative Composition

Utrogestan contains the active ingredient: Progesterone (micronised) 200 mg.

Excipient with known effect.

Soyabean lecithin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Utrogestan 200 soft capsule is an ovoid, slightly yellow, soft capsule, containing a whitish oily suspension.

4 Clinical Particulars

4.1 Therapeutic Indications

Utrogestan 200, soft capsules are indicated for:

Luteal phase support.

Luteal Support of Assisted Reproductive Technology (ART) cycles.

Support during pregnancy.

Prevention of preterm birth in women with singleton pregnancy who have a short cervix (midtrimester sonographic cervix ≤ 25 mm) and/or a history of spontaneous preterm birth.
Treatment of unexplained threatened miscarriage in women with bleeding in the current pregnancy and a history of at least three or more previous miscarriages.
Use in women with less than three miscarriages may be warranted in those with reduced chances of future pregnancy such as those undergoing IVF treatment with limited viable egg and/or embryo availability or advanced fertility age. However, the benefit of treatment in clinical trials was limited to women with three or more miscarriages. (See Section 5 Pharmacological Properties, Clinical trials, Treatment of unexplained threatened miscarriage).

4.2 Dose and Method of Administration

Adults.

Luteal phase support (LPS).

The recommended dosage is 600 mg/day, in three divided doses, from the day of embryo transfer until at least the 7th week of pregnancy and not later than the 12th week of pregnancy.

Prevention of preterm birth (PTB).

The usual dose is 200 mg/day, recommended at bedtime. Treatment can be initiated during the second trimester (16-24 weeks gestation) and is to be continued to the end of the 36th week of gestation or until delivery.

Threatened miscarriage.

The usual dose is 400 mg twice a day (morning and night). Treatment should be initiated at the first sign of vaginal bleeding during the first trimester of pregnancy (see Section 4.4 Special Warnings and Precautions for Use) and should continue to at least the 16th week of gestation.

Children.

Not applicable.

Elderly.

Not applicable.

Method of administration.

Vaginal. Each capsule of Utrogestan must be inserted deep into the vagina.
The average dosage is 200 to 800 mg of progesterone per day to be introduced deep into the vagina. This may be increased, depending on the patient's response.

In partial luteal insufficiency (dysovulation).

Treatment should be given for 10 days per cycle, usually from days 17 to 26 of the cycle, at a dosage of 200 mg of progesterone daily.

In sterility oocyte donation program.

The recommended dosage of progesterone is 100 mg on day 13 and 14 of the transfer cycle, followed by 100 mg of progesterone in the morning and evening, from days 15 to 25 of the cycle. From day 26, the dose should be increased, in early pregnancy, weekly, from 100 mg of progesterone per day up to a maximum of 600 mg of progesterone per day, as three divided doses. This dosage should be continued until day 60.

In luteal phase supplementation during ART (IVF).

Treatment should be started latest from the evening of the transfer, as 600 mg of progesterone in three divided doses, morning, midday and evening.

In the prevention of premature birth.

The dosage is 200 mg daily in the evening at bedtime. Treatment can be initiated during the second trimester (16 - 24 weeks gestation) and is to be continued to the end of the 36th week of gestation or until delivery.

In the treatment of unexplained threatened miscarriage.

The usual dose is 400 mg twice a day (morning and night). Treatment should be initiated at the first sign of vaginal bleeding during the first trimester of pregnancy and should continue to at least the 16th week of gestation.

4.3 Contraindications

Utrogestan should not be used in individuals with any of the following conditions:
Known allergy or hypersensitivity to progesterone or to any of the excipients.
Severe hepatic dysfunction.
Undiagnosed vaginal bleeding.
Known missed abortion or ectopic pregnancy.
Mammary or genital tract carcinoma.
Thromboembolic or thrombophlebitis disorders.
Cerebral haemorrhage.
Porphyria.

4.4 Special Warnings and Precautions for Use

During pregnancy, Utrogestan should be used for the recommended timeframes for each indicated use (see Section 4.2 Dose and Method of Administration). Utrogestan should only be used by the vaginal route. Cases of cytolytic liver damage and cases of gravidic cholestasis were exceptionally reported during the administration of micronised progesterone during the 2nd and 3rd trimesters of pregnancy.
Utrogestan is not suitable for use as a contraceptive.
Women should insert each capsule deep into the vagina.
If uterine bleeding is present, do not prescribe before establishing a cause, particularly with endometrial investigations.
Patients must be monitored closely if they have a past history of venous thrombosis.
Treatment should be discontinued upon diagnosis of a missed abortion.
Utrogestan should be used cautiously in patients with conditions that might be aggravated by fluid retention (e.g. hypertension, cardiac disease, renal disease, epilepsy, migraine, asthma); in patients with a history of depression, diabetes, mild to moderate hepatic dysfunction, migraine or photosensitivity and in breastfeeding mothers.
There is limited evidence that supplementation with vaginal progesterone reduces the risk of preterm birth in women with twin/multiple pregnancy who have short cervix (midtrimester sonographic cervix ≤ 25 mm) and/or a history of spontaneous preterm birth.
There is insufficient evidence to recommend the use of progesterone in women with preterm labour or 'other' risk factors for preterm birth.
Other known causes of threatened or recurrent miscarriage should be ruled out before initiating treatment in women with threatened or recurrent miscarriage.
Utrogestan contains soya lecithin which may cause hypersensitivity reactions (urticaria and anaphylactic shock).

Use in the elderly.

No data available.

Paediatric use.

There is no experience in children as there is no relevant indication for use of Utrogestan in children. Utrogestan has not been evaluated in adolescents with child-bearing potential.

Effect on laboratory tests.

Utrogestan may affect the results of laboratory tests of hepatic and/or endocrine functions.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Progesterone is metabolised primarily by the liver. Caution should be taken with drugs that are P450 enzyme inducers and inhibitors.
Metabolism of Utrogestan is accelerated by rifamycin, an antibacterial agent.
The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC50 < 0.1 microM), a known inhibitor of cytochrome P450 3A4. These data therefore suggest that ketoconazole may increase the bioavailability of progesterone. The clinical relevance of the in vitro findings is unknown.
Combination with other medicinal products may decrease progesterone metabolism which may alter its effect.
This applies to:
potent enzyme inducers such as barbiturates, antiepileptics (phenytoin), rifampicin, phenylbutazone, spironolactone and griseofulvin. These medicinal products increase hepatic metabolism;
some antibiotics (ampicillins, tetracyclines): changes in the intestinal flora leading to a change in the steroid enterohepatic cycle.
Utrogestan may interfere with the effects of bromocriptine and may raise the plasma concentration of cyclosporin.
As these interactions may vary between people, the clinical results are not necessarily predictable.
Progestogens, but not natural progesterone may impair glucose tolerance and, because of this, increase requirements for insulin or other antidiabetic agents in diabetic patients.
The bioavailability of progesterone may be reduced by smoking and increased by alcohol abuse.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Exogenously administered progesterone has been shown to inhibit ovulation in a number of species and it is expected that high doses given for an extended duration would impair fertility until the cessation of treatment.
(Category A)
Progesterone crosses the placenta. No association has been found between the maternal use of progesterone in early pregnancy and fetal malformations. Data on the risk of fetal effects with exposure in later stages of pregnancy are limited. Male and female genital abnormalities (hypospadias and virilisation) have been observed in fetuses of animals treated with progesterone during gestation.
Detectable amounts of progesterone enter the breast milk. Therefore, Utrogestan should not be used during lactation.

4.7 Effects on Ability to Drive and Use Machines

Cases of drowsiness and dizzy sensations have been reported for the oral form.
Drivers and machine operators in particular, are alerted to the risks of drowsiness and/or dizziness associated with oral use of this medicinal product. These problems can be avoided by taking the capsules at bedtime.

4.8 Adverse Effects (Undesirable Effects)

No major local intolerance issues have been reported during the different clinical trials even if some burning, pruritus or fatty discharge have been observed and reported in the literature; incidences were extremely low.
No systemic side effects, in particular somnolence or dizziness (observed with the oral form), have been reported during clinical studies at the recommended dosages.
No significant safety concerns for the mother or for the foetus were identified with vaginally administered Utrogestan during pregnancy. Maternal outcomes were unaffected. Treatment-related adverse effects were generally mild and transient, and the incidence was no greater than those reported for placebo or no treatment. The adverse effect profile was consistent with the established safety profile of Utrogestan for ART.
The beneficial effects of progesterone to prevent preterm birth in women with a short cervix and/or a history of preterm birth is expected to improve neonatal outcomes. There is no evidence that fetal progesterone exposure in the 2nd and 3rd trimester adversely affects childhood neurodevelopmental outcomes.
Consistent with the well-established safety profile of vaginally administered progesterone for support in the luteal phase and for support during pregnancy for women at risk of preterm birth, progesterone for the prevention of miscarriage does not appear to increase the risk of congenital malformations. Incidence of adverse neonatal outcomes and serious maternal adverse events were low with no differences observed between progesterone and placebo groups during the 1st and 2nd trimester. The adverse effect profile remains unchanged regardless of the timing or duration of treatment during pregnancy with beneficial effects of progesterone expected to increase the number of live births in women with threatened miscarriage or a history of recurrent miscarriage. See Tables 1 and 2.

Post-marketing experience.

The information given in Table 3 is based on extensive post marketing experience from vaginal administration of progesterone.
Adverse effects have been ranked under headings of frequency using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

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.

4.9 Overdose

Symptoms of overdose (more frequent with the oral route of administration) may include somnolence, dizziness, euphoria or dysmenorrhoea. Treatment is observation and, if necessary, symptomatic and supportive measures should be provided.
Although no overdose has been reported to date for the vaginal form, the adverse effects described above are usually signs of overdose. These disappear without treatment when the dosage is reduced.
In case of overdose, immediately contact the Poisons Information Centre (in Australia, call 13 11 26) for advice.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Progesterone is a naturally occurring steroid hormone that is secreted by the ovary, placenta and adrenal gland. It acts on the endometrium by converting the proliferating phase to the secretory phase. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo, and once an embryo is implanted, progesterone acts to maintain the pregnancy. As well as gestagenic actions, progesterone also has anti-estrogenic, slightly anti-androgenic and anti-aldosterone effects.

Clinical trials.

Luteal phase support.

Two company sponsored studies have been conducted to investigate efficacy of Utrogestan for luteal phase support.
1. Study Kleinstein 2002 was an open, multicentre, comparative controlled, randomised, parallel group phase III trial that compared the efficacy and safety of vaginal Utrogestan 200 mg three times daily and vaginal 1.125 g Crinone 8% gel twice daily, for up to 12 weeks, in providing luteal phase support to women undergoing IVF [Kleinstein 2005].
The primary endpoint was the ongoing pregnancy rate at the end of the 12th week of gestation. The implantation and abortion rates and the rate of withdrawals, overall or at the respective visits, were considered as secondary study endpoints.
Fifty five (55) patients in the Utrogestan group and forty seven (47) patients in the progesterone gel group completed the study. These were all women with ongoing pregnancies at or beyond the 12th week of gestation. Ongoing pregnancy rates were 25.2% (95% confidence interval [CI]: 19.6%-31.5%) for the Utrogestan group and 22.2% (95% CI: 16.8%-28.4%) for the progesterone gel group (Figure 1). The odds ratio (OR) (calculated on the per protocol population) for an intact pregnancy at the end of 12th week of gestation was 1.185 (90% CI: 0.733-1.833) when the Utrogestan group was compared with the progesterone gel group. According to the prespecified criteria, the pregnancy rate in the Utrogestan group was demonstrated to be noninferior to that in the progesterone gel group (lower limit of the 90% confidence interval > -0.1).
The implantation and abortion rates were also considered to be equivalent between the Utrogestan 200 group and Crinone 8% group (Table 4).
More than 90% of women rated overall tolerability of the study drugs as "very good" or "good". Similarly, acceptance of either treatment was positively assessed in > 90% of women by the physicians. Nevertheless, both items indicated an overall significant difference (P < 0.0001) of the effect index, as calculated from rank sums, in favour of Utrogestan.
These efficacy findings are consistent with the company sponsored bioavailability study showing that the vaginal bioavailability of micronised progesterone following administration of a Utrogestan 200 mg capsule and Crinone 8% gel (90 mg progesterone) in young healthy women was therapeutically at least equivalent to that of the vaginal gel [Kleinstein 2002].
The role of progesterone for luteal phase support in stimulated IVF cycles is well established and supported by several recent meta-analyses [Nosarka 2005; Polyzos 2010; Pritts and Atwood 2002; van der Linden 2012, van der Linden 2015, Zarutskie and Phillips 2009, Lin 2012]. However, several meta-analyses included data from RCTs with an unclear or high risk of bias. In general, findings from the meta-analyses showed no significant differences in clinical pregnancy rate between the different formulations of vaginal progesterone (gel, capsule, inserts, pessaries) [Polyzos 2010, Zarutskie and Phillips 2009] but the relative benefit of the various routes of administration (oral, IM, vaginal) is unclear. Despite this, the vaginal route is often preferred because of better patient comfort [Vaisbuch 2014].
The use of progesterone for luteal phase support was recently reviewed in detail by the UK National Institute for Care Excellence (NICE) in 2013, to provide guidelines on treatment options for luteal phase support in fertility treatments. This was a significant assessment, which involved detailed review of all existing published evidence on the use of progesterone for luteal phase support. Overall, the evidence from the current published clinical studies was judged to be of low to very low quality; largely due to poor reporting on the details of the studies and lack of reported power calculations. Studies may have been underpowered for many of the reported outcomes, as shown by the wide confidence intervals around power estimates. However, it is clear that much of the evidence is over 20 years old and new research is unlikely to be conducted because of the well accepted role of luteal phase support in IVF treatment.
Notwithstanding any weaknesses in the data, the NICE 2013 guidelines, which are consistent with the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) guidelines, recommend the following:
There is evidence that luteal phase support with progesterone is associated with significantly more live full term singleton births and clinical pregnancies than placebo or no support. Progesterone is therefore the drug of choice recommended for luteal phase support.
There was no significant difference in the number of clinical pregnancies and live full term singleton births when comparing the different types of drugs used for luteal phase support. However, the evidence showed that the use of hCG for luteal phase support was associated with an increased risk of ovarian hyperstimulation syndrome compared with the use of progesterone. Therefore, hCG is not recommended for luteal phase support.
In terms of duration of treatment, luteal phase support should be offered for up to 8 weeks after embryo transfer and patients should be informed that there is no evidence for continuing luteal phase support after this time.
2. Study Salat-Baroux 1988 was a one arm, prospective study that evaluated endometrial morphology and pregnancy outcomes following the administration of Utrogestan and oestradiol in women without ovarian function participating in an oocyte donation program.
The aim of this clinical study was to demonstrate adequate endometrial maturation in women lacking ovaries after the vaginal administration of progesterone and pregnancy after the transfer of frozen embryos, thawed in the context of oocyte donation.
One capsule of Utrogestan (100 mg natural micronised progesterone) was inserted into the vagina by the subject on days 13 and 14 in the evening. On days 15 to 25 an additional capsule was inserted in the morning. The dose was then regularly increased to 300, 400, 500, and 600 mg/day maximum until day 60.
The primary outcome measure was the effectiveness of vaginal progesterone as assessed by plasma progesterone concentrations (days 13, 15 and 21) and endometrial histology.
Endometrial biopsies on days 21 or 22 of a substitution cycle were found to be, on average, typical of endometria on days 21 ± 2 (average ± SD) of a normal 28 day menstrual cycle in 18 of the 22 women. In the other 4 women, 3 cases of moderate hypotrophy and 1 case of severe hypotrophy were observed.
There were 11 pregnancies out of 32 transfers (34%).
In conclusion, findings from this clinical trial demonstrated that the vaginal administration of natural micronised progesterone enables an adequate maturation of the endometrium in women without functioning ovaries.
These findings are supported by a meta-analysis of 9 RCTs (1620 women) [van der Linden M 2012] of varying quality comparing vaginal versus IM progesterone in women undergoing ART. The meta-analysis showed no differences for ongoing and clinical pregnancy or live birth rate between vaginal progesterone (gel or capsule) and IM progesterone as luteal support for women undergoing ART. Although a meta-analysis of data from 22 RCTs (3451 women) of moderate risk of bias found insufficient evidence to recommend any one particular protocol for endometrial preparation over another with regard to pregnancy rates after embryo transfers, there was evidence of a lower pregnancy rate when progesterone supplementation is commenced before oocyte retrieval in oocyte donation cycles.
The role for progesterone as support during the luteal phase of IUI cycles is not well established. Although progesterone and hCG are both used for luteal phase support, progesterone may be the preferred over hCG because of the potential for ovarian hyperstimulation syndrome with hCG [van der Linden 2011]. No company sponsored studies were conducted to support this indication. Two meta-analyses [Hill 2013; Miralpeix 2014] including the same 5 open label RCTs of mixed quality, evaluated vaginal progesterone as luteal support in the following formulations: gel (Crinone 8% 90 mg/day, 2 RCTs), capsules (Utrogestan 600 mg/day, 1 RCT), or suppositories (Cyclogest 400 mg/day, 2 RCTs). Findings from these meta-analyses showed that vaginal progesterone increased the likelihood of clinical pregnancy and live birth per cycle and may be of benefit in women undergoing ovulation induction with gonadotropins, but not clomiphene citrate, during IUI.
Moreover recently, a retrospective evaluation of the luteal phase of 579 IUI cycles from 2010 to 2013 was conducted to determine the effect of luteal phase support on clinical pregnancy and live birth rates after ovulation induction and IUI [Oktem 2014]. Ovarian stimulation was performed with gonadotropins, and recombinant hCG was used for ovulation triggering. The use of vaginal progesterone gel (Crinone) or micronised progesterone vaginal capsules (Besins progesterone capsules) were found to significantly improve clinical pregnancy rates.

Support during pregnancy.

Prevention of pre-term birth. Study UTRO-200-PTD (MISTERI) 2014 was an open-label, multicentre, one-arm phase III study that evaluated whether the prophylactic use of 200 mg vaginal progesterone daily in weeks 19-34 of pregnancy reduces the rate of preterm birth in women at high risk for preterm birth.
The primary objective of the study was to improve obstetric outcomes by prolonging pregnancy and thereby reducing the rate of preterm birth (birth prior to 34+0 weeks) with prophylactic use of 200 mg/day natural progesterone (Utrogestan) in weeks 19-34 of gestation in women at high risk for preterm birth compared to the population at risk of preterm birth.
All patients (N = 220) who enrolled in the study received 200 mg/day Utrogestan vaginally for 10 to 15 weeks, depending on the gestational age at enrolment. Treatment was started no earlier than week 19+0 and no later than week 24+0 of pregnancy and the maximum duration of treatment was 15 weeks (weeks 19 to 34 of gestation).
One hundred and ten (110) patients were grouped as:
patients with a shortened cervix (uterine cervix length of > 10 and < 25 mm at weeks 18-24 of gestation); and
patients with anamnestic risk factors (a prior preterm birth or premature rupture of membranes).
Patients with both risk factors were included in the shortened cervix group.
The investigators concluded that, according to the data generated in the study, the risk of preterm birth prior to 34 weeks was effectively reduced by treatment with vaginal Utrogestan 200 mg capsules in patients with preterm birth risk factors (cervical shortening and medical history of preterm birth and/or preterm premature rupture of membranes).
The company-sponsored study is supported by systematic reviews, meta-analyses and numerous investigator-sponsored studies similarly showing a significantly lower risk of preterm birth before 34 weeks gestation in women with a short cervix and/or a history of preterm birth.

Short cervix and/or history of preterm birth.

Fonseca 2007 was a randomised, double-blind, placebo-controlled trial that examined the effects of vaginal progesterone for the prevention of preterm birth in women with a short cervix. In this study women were allocated to receive either Utrogestan 200 mg/day or placebo from 24 to 34 weeks gestation with the primary aim to measure the frequency of spontaneous preterm delivery at < 34 weeks of gestation. Patients treated with Utrogestan had a lower rate of preterm delivery (< 34 weeks) than those in the placebo group [19.2% (24/125) vs 34.4% (43/125)].
Norman 2016 [OPPTIMUM study] was a double-blind, placebo-controlled randomised clinical trial conducted in a heterogeneous group of women at risk of PTB to determine whether vaginal progesterone (200 mg daily from 22-24 weeks to 34 weeks of gestation) reduced the risk of preterm birth. The study also assessed whether progesterone prophylaxis affects neonatal and childhood outcomes.
Although the odds ratio (OR) was in the direction of benefit, administration of progesterone did not significantly alter the risk of obstetric outcomes (fetal death or birth < 34 weeks; OR 0.86) or neonatal outcome (a composite of death, brain injury or bronchopulmonary dysplasia; OR 0.62) in this heterogeneous population of women at risk of PTB. Progesterone prophylaxis for preterm birth had no effect on childhood outcomes (at 2 years).
The OPPTIMUM trial reported a non-significant 38% reduction in the risk of neonatal death or serious neonatal morbidity, which is very similar to the 43% significant reduction in the risk of composite neonatal morbidity and mortality found in a previous Individual Patient Data (IPD) Meta-analysis by Romero (RR 0.59, 95% CI 0.38-0.91) (Romero 2012).
In a subgroup analysis of women with a short cervix ≤ 25 mm, the point estimates for neonatal composite effects in the OPPTIMUM study (OR 0.54; CI 0.25-1.16) was comparable to the RR of 0.57 in the IPD meta-analysis by Romero and colleagues (Romero 2012).
It is noteworthy that the OPPTIMUM trial was underpowered to detect a meaningful difference between vaginal progesterone and placebo in the subgroup of women with a CL ≤ 25 mm. Therefore, a new Individual Patient Data level meta-analysis including OPPTIMUM trial results, was mandatory to understand what the totality of evidence indicates, particularly within subgroups of interest and to address the effect of vaginal progesterone for the most powerful risk factor (short cervix), as suggested by the authors in the publication (Norman 2016).
A first aggregate meta-analysis, including the OPPTIMUM data, was published shortly after the release of the OPPTIMUM study data to quantify the efficacy of vaginal progesterone to improve perinatal morbidity and mortality in asymptomatic women with a singleton gestation and a midtrimester short cervix (Romero 2016). In 5 RCTs including 974 women, vaginal progesterone was associated with a 34% reduction in the risk of PTB ≤ 34 weeks or fetal death (RR 0.60, 95% CI, 0.52-0.83, P=0.0005). Composite neonatal morbidity and mortality was also significantly reduced in women treated with vaginal progesterone, along with a reduction in RDS, birth weight < 1500 g and admission to NICU.
Following on from the 2016 aggregate meta-analysis, an in-depth individual participant data (IPD) meta-analyses, which included individual patient data from the OPPTIMUM trial, reported with Level I evidence that vaginal progesterone reduces the risk of PTB and improves perinatal outcomes in singleton gestation with a midtrimester short cervix (Romero 2018). Vaginal progesterone had no effect on childhood neurodevelopmental outcomes.
Several further meta-analyses on the use of progesterone in the prevention of preterm birth have been published, each of which further supports the use of vaginal progesterone in the prevention of preterm birth in pregnant women with a midtrimester short cervix with reductions in neonatal morbidity and mortality (Romero 2017; Romero 2012; Conde-Agudelo 2018; Jarde 2017a; Jarde 2017b; Schuit 2014; Dodd 2013; Velez Edwards 2013; Sotiriadis 2012; Likis 2012; Mckenzie 2006). Together these findings suggest that routine screening of women to detect short cervical length at the mid-trimester and prophylactic administration of progesterone to those found to have a short cervix is warranted.
Meta-analyses of randomised controlled trials have also demonstrated that daily vaginal progesterone, initiated at around 16 weeks' gestation, prevents PTB in women with a history of spontaneous PTB (Conde-Agudelo 2018; Saccone 2017; Jarde 2017a; Jarde 2017b; Oler 2017; Dodd 2013; Sotiriadis 2012; Likis 2012; Dodd 2005).
A 2013 Cochrane review assessed the benefits and harms of progesterone for the prevention of preterm birth in women with a history of preterm birth (Dodd 2013). The findings, all significantly in favour of progesterone, included a reduction in the risk of preterm birth at < 34 and < 37 weeks gestation and a significant increase in pregnancy prolongation, significant improvements in perinatal mortality, infant birthweight, use of assisted ventilation, necrotising enterocolitis, neonatal death and admission to NICU (Dodd 2013).

Treatment of unexplained threatened miscarriage.

The PROMISE trial (Coomarasamy 2015) was designed to evaluate the effects of progesterone in the 1st trimester, not during the luteal phase, and because progesterone treatment was initiated only after urinary pregnancy test was confirmed, the study did not address whether progesterone supplementation would be more effective in reducing the risk of miscarriage if administered during luteal phase of the cycle, before confirmation of pregnancy.
Progesterone supplementation in early pregnancy has been attempted in two contexts: the first is to prevent miscarriages in asymptomatic women who have a history of recurrent miscarriages (as in the PROMISE trial) and the second was to rescue a pregnancy in women who have started to bleed during early pregnancy (Wahabi 2018). As no beneficial effect of progesterone in women with a history of unexplained recurrent miscarriages was found in PROMISE, the second scenario was evaluated in the PRISM trial, the largest randomised trial conducted evaluating progesterone in women with early pregnancy bleeding.
The intervention in the PRISM trial was Utrogestan 400 mg administered vaginally twice daily or placebo pessaries. The 800 mg daily dose, divided into 2 doses, is considered to be a clinically effective dose based on luteal phase support data. Progesterone therapy continued until 16 weeks' gestation. At this critical luteoplacental juncture of pregnancy, placental progesterone is biologically more important than luteal progesterone.
The primary outcome of the PRISM trial was a live birth after at least 34 weeks gestation. Live births were greater in the progesterone group (75% in the progesterone group vs. 72% in the placebo group (RR, 1.03; 95% CI, 1.00-1.07, p=0.08)) and this primary outcome achieved borderline significance (Coomarasamy 2020a, HTA, Coomarasamy 2019, NEJM PRISM Trial). Progesterone resulted in an additional 2 live births per 100 women at ≥ 34 weeks of gestation compared with placebo (Coomarasamy 2020b, ACOG). Live birth rate after 24 weeks of gestation was 66% in the progesterone group compared with the 63.3% in the placebo group (relative rate, 1.04: 95% CI, 0.94-1.15: absolute risk difference, 2.5 percentage points: 95% CI, -4.0 to 9.0).
A subgroup effect by previous history of miscarriage was observed in pre-specified subgroup analysis. Analysis revealed a biological gradient, whereby women with 1 or 2 previous miscarriages gained some benefit and those with ≥ 3 previous miscarriages received a considerably significant benefit. In women with threatened miscarriage and a history of 1 or more miscarriage(s), the number needed to treat for 1 additional live birth is 20. In women with a history of 3 or more miscarriages, the number needed to treat is 8. The biological gradient of progesterone combined with the borderline significant live birth rate provides assurance of the positive effects of progesterone in women at high-risk of miscarriage. See Figure 2.
In summary, the dual risk factors of early pregnancy bleeding and a history of one or more previous miscarriage(s) identified high-risk women in whom progesterone may be of benefit. It is suggested that the information should be communicated to women at high risk of miscarriages to enable shared decision-making and consider offering to women with vaginal bleeding and a history of 1 or more previous miscarriage(s) a course of treatment with vaginal micronized progesterone 400 mg twice daily, started at the time of presentation with vaginal bleeding and continued to 16 completed weeks of gestation. (NICE 2021) In the United Kingdom, they estimated that implementing this treatment strategy would result in an additional 8450 live births per year and believed that a woman at high risk of having a miscarriage may not need absolute scientific certainty to choose to have this treatment (Coomarasamy 2020b, ACOG).
A Cochrane network meta-analysis including seven randomised trials involving 5682 confirmed that vaginal micronized progesterone may increase the live birth rate for women with a history of one or more previous miscarriages and early bleeding pregnancy (Devall 2021). For women with one or more previous miscarriages and early pregnancy bleeding, vaginal micronized progesterone increased the live birth rate compared to placebo (RR 1.08, 95% CI 1.02 to 1.15, high-certainty evidence). (Devall 2021).

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, micronised progesterone is absorbed by the digestive tract. Pharmacokinetic studies conducted in healthy volunteers have shown that after oral administration of two 100 mg capsules (200 mg), plasma progesterone levels increased to reach the Cmax of 13.8 nanogram/mL ± 2.9 nanogram/mL in 2.2 ± 1.4 hours. The elimination half-life observed was 16.8 ± 2.3 hours.
Although there were interindividual variations, the individual pharmacokinetic characteristics were maintained over several months, indicating predictable responses to the drug.
Following vaginal administration, micronised progesterone is absorbed rapidly and achieves stable plasma levels in the range of 4-12 nanogram/mL, depending on the daily dose, with much less intersubject variation than following oral administration.

Distribution.

Following vaginal administration of micronised progesterone, relatively high concentrations of progesterone are found in the uterus and nearby tissues with correspondingly low systemic exposure. Progesterone enters both the lymph system and the blood vessels, as outlined for the uterine first-pass effect. Progesterone is approximately 96-99% bound to serum proteins, primarily to serum albumin (50-54%) and transcortin (corticosteroid binding globulin) (43-48%).

Metabolism.

Progesterone is metabolised primarily by the liver. Following oral administration, the main plasma metabolites are 20α hydroxy-Δ4α-prenolone and 5α-dihydroprogesterone. Some progesterone metabolites are excreted in the bile and these may be deconjugated and further metabolised in the gut via reduction, dehydroxylation and epimerisation.
The main plasma and urinary metabolites are similar to those found during the physiological secretion of the corpus luteum.
Following vaginal administration, only low plasma levels of pregnanolone and 5α-dihydroprogesterone are detected, due to the lack of first-pass metabolism.

Excretion.

Urinary elimination is observed for 95% in the form of glycuroconjugated metabolites, mainly 3α, 5β-pregnanediol (pregnandiol).

5.3 Preclinical Safety Data

Genotoxicity.

Progesterone did not induce chromosomal aberrations or sister chromatid exchanges in cultured human cells nor chromosomal aberrations or DNA strand breaks in rodent cells. Progesterone did not induce dominant lethal mutations in mice or chromosomal aberrations in the bone marrow of rats in vivo although in vivo studies for chromosome damage have yielded positive results in mice at oral doses of 1000 mg/kg and 2000 mg/kg.
Weak clastogenic activity was found for progesterone in the rat hepatocyte micronucleus test after treatment with a high oral dose (100 mg/kg). Studies on transformation of rodent cells in vitro were inconclusive. Variable results were obtained in the mouse lymphoma tk assay. Progesterone was not mutagenic to bacteria.

Carcinogenicity.

Progesterone has been shown to induce/ promote the formation of ovarian, uterine, mammary, and genital tract tumours in animals. The clinical relevance of these findings is unknown. Literature data provides no indication of potential carcinogenicity in humans.
When implanted into female mice, progesterone produced mammary carcinomas, ovarian granulosa cell tumours and endometrial stromal sarcomas. In dogs, long-term intramuscular injections produced nodular hyperplasia and benign and malignant mammary tumours. Subcutaneous or intramuscular injections of progesterone decreased the latency period and increased the incidence of mammary tumours in rats previously treated with a chemical carcinogen.
The exposure to women remains always in the physiological range of progesterone and is regarded as hormone replacement therapy whatever the indication.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sunflower oil, lecithin, gelatin, glycerol, titanium dioxide, 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

In Australia, information on the shelf-life can be found on the public summary of the Australia Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.
Do not refrigerate.

6.5 Nature and Contents of Container

Utrogestan is supplied in a PVC/aluminium blisters packaged in an outer carton.
Utrogestan 200 is available in pack sizes of 7 (trade or starter pack), 14, 15, 21, 28, 30, 42, 45, 56, 84 or 90 capsules*.
*Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed in accordance with local requirements.

6.7 Physicochemical Properties

Progesterone is a white or almost white crystalline powder or colourless crystals, is practically insoluble in water, freely soluble in ethanol and sparingly soluble in acetone and in fatty oils.

Chemical structure.


Chemical name: pregn-4-ene-3,20-dione.
Molecular formula: C21H30O2.
MW: 314.5.

CAS number.

57-83-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes