Consumer medicine information

PROMETRIUM

Progesterone

BRAND INFORMATION

Brand name

Prometrium Capsules

Active ingredient

Progesterone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using PROMETRIUM.

What is in this leaflet

This leaflet answers some common questions about Prometrium.

The leaflet 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 taking Prometrium against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What Prometrium is used for

Prometrium is provided as a soft capsule that contains the natural female hormone, progesterone for oral use.

Prometrium is for women for the treatment of menstrual abnormalities or secondary amenorrhoea (no menstrual periods) and as hormone replacement therapy (HRT) in combination with oestrogen in postmenopausal women with an intact uterus (womb).

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

Prometrium is available only with a doctor’s prescription.

This medicine is not addictive.

This medicine is not a contraceptive.

Before you take Prometrium

When you must not take it

Do not take Prometrium if you have an allergy to:

  • any medicine containing progesterone
  • any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include:

  • skin rash, itching or hives
  • swelling of the face, lips, tongue or other parts of the body
  • shortness of breath, wheezing or difficulty breathing.

Do not take Prometrium if you have or have had any of the following conditions:

  • unusual vaginal bleeding that has not been evaluated by your doctor
  • 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).

Do not take Prometrium if you are pregnant or intend to become pregnant.

If you get pregnant while taking Prometrium, stop taking it straight away and tell your doctor.

Do not take Prometrium if you are breast-feeding.

Do not give Prometrium to a child of any age.

Do not take Prometrium after the expiry date printed on the pack.

Do not take Prometrium if the packaging is torn, shows signs of tampering, or if the product does not look quite right.

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

If you are not sure whether you should start taking Prometrium talk to your doctor.

Before you start to take it

Before starting or recommencing progesterone therapy, a physical examination should have been performed including special attention to the breasts, abdomen and pelvic organs.

Tell your doctor or pharmacist if you have allergies to:

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

You must tell your doctor or pharmacist if you have or have had any of the following problems:

  • epilepsy
  • migraine
  • high blood pressure
  • asthma
  • heart, liver or kidney disease
  • diabetes
  • skin sensitive to light
  • history of depression.

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

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines may affect the way other medicines work.

Some medicines may interfere with progesterone if taken at the same time. These include:

  • Carbamazepine, Phenobarbital and Phenytoin (medicines for epilepsy)
  • Rifampicin
  • Phenylbutazone
  • Spironolactone
  • Griseofulvin
  • Some antibiotics including ampicillins and tetracyclines
  • Bromocriptine
  • Cylosporin
  • Ketoconozole

These medicines may be affected by Prometrium 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.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Prometrium.

How to take Prometrium

How much to take

Your doctor or pharmacist will tell you how many capsules you need to take each day.

For women receiving hormone replacement therapy in conjunction with oestrogen with an intact uterus (womb), the usual dose is 200 mg/day at bedtime on days 15 to 26 of your cycle. You will usually have a few days withdrawal bleeding (like a period) after this time. Alternatively 100 mg can be taken at bedtime, from days 1 to 25 of each cycle, withdrawal bleeding being less with this treatment schedule.

For women with secondary amenorrhea (no menstrual periods), the treatment may be taken as a single daily dose of 400 mg at bedtime, for 10 days.

The standard daily dose is 200 to 300 mg of progesterone taken in one or two doses (i.e. 200 mg in the evening and another 100 mg in the morning, if needed).

In menstrual irregularities due to ovulation disorders, treatment is administered over 10 days per menstrual cycle, usually from days 17 to 26 inclusive.

Prometrium is to be taken by mouth and swallowed whole with a glass of water.

Do not take Prometrium with food as this may affect the way Prometrium works.

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

How long to take it

The use of Prometrium may be continued for up to 10 days.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to, as usual.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

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

If you are not sure what to do, talk to your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much Prometrium. Do this even if there are no signs of discomfort or poisoning.

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

While you are taking Prometrium

Things you must do

Tell any other doctors or pharmacists who are treating you that you are taking Prometrium.

If you are about to start taking any new medicines, tell your doctor or pharmacist that you are taking Prometrium.

Take special care and tell your doctor straight away if you experience any of these symptoms during treatment or even a few days after the last dosage:

  • pains in your calves or chest, a sudden shortness of breath or coughing up blood indicating possible clots in the legs, heart or lungs
  • severe headache or vomiting, dizziness, faintness or changes in vision or speech, weakness or numbness of an arm or leg indicating possible clots in the brain or eye
  • worsening symptoms of depression.

Things you must not do

Do not give Prometrium to anyone else, even if they have the same condition as you.

Do not take Prometrium to treat any other complaints unless your doctor has told you to.

Do not stop taking Prometrium or lower the dosage without checking with your doctor or pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how Prometrium affects you.

Some people may experience drowsiness or dizziness. Make sure you know how you react to Prometrium 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.

Side effects

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

Prometrium helps most people 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.

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

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • headache
  • abnormal breakthrough bleeding and/or vaginal bleeding or spotting or changes in cervical secretions
  • any significant change in your menstrual cycle, including loss of menstruation
  • unusual tiredness or weakness or weight gain
  • acne, breast pain or tenderness
  • mild mood changes, changes in libido and insomnia

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • constipation
  • breast disorders (e.g. breast pain, breast swelling and breast tenderness)
  • headache, dizziness and drowsiness
  • mental depression
  • skin rash, itchiness (pruritus)

The above list includes serious side effects which may require medical attention. Serious side effects are rare.

If any of the following happen, stop taking Prometrium and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • Migraine
  • Loss of or change of speech, coordination or vision, pain or numbness in chest, arm or leg; unexplained shortness of breath, any symptoms of blood clots (thrombosis)
  • Yellowing of skin or eyes (jaundice)

These are very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that is making you feel unwell.

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

Do not be alarmed by the list of possible side effects.

You may not experience any of them.

After taking Prometrium

Storage

Keep this medicine in its original packaging until it is time to take them.

Keep this medicine in a cool dry place where the temperature stays below 30°C. DO NOT REFRIGERATE.

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

Do not leave it in the car or on window sills.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that are left over.

Product description

What it looks like

Prometrium 100 mg, soft capsule is a round, slightly yellow soft capsule, containing a whitish oily suspension. Prometrium 100 mg, soft capsule is supplied in blister strips packaged in an outer carton. Each carton contains 14, 15, 28, 30, 56, 84 or 90 capsules*.

Prometrium 200 mg, soft capsule is an ovoid slightly yellow soft capsule, containing a whitish oily suspension. Prometrium 200 mg, soft capsule is supplied in blister strips packaged in an outer carton. Each carton contains 7, 14, 15, 21, 28, 30, 42, 45, 56, 84 or 90* capsules.

* Not all pack sizes may be marketed.

Ingredients

Active ingredient:

  • progesterone 100 mg or 200 mg

Inactive ingredients:

  • sunflower oil
  • soya lecithin
  • gelatin
  • glycerol
  • titanium dioxide

Sponsor

Prometrium is supplied in Australia by:

Besins Healthcare Australia Pty Ltd
Level 23 Governor Macquarie Tower
1 Farrer Place
Sydney
NSW 2000

This leaflet was prepared in April 2016.

Prometrium 100 mg, soft capsule AUST R 232818
Prometrium 200 mg, soft capsule AUST R 232823

BRAND INFORMATION

Brand name

Prometrium Capsules

Active ingredient

Progesterone

Schedule

S4

 

Name of the medicine

Progesterone (micronised).

Excipients.

Sunflower oil, soya lecithin, gelatin, glycerol and titanium dioxide.

Description

Chemical name: pregn-4-ene-3,20-dione. Molecular formula: C21H30O2. MW: 314.5. CAS: 57-83-0. 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.

Pharmacology

Pharmacodynamics.

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 antiestrogenic, slightly antiandrogenic and antialdosterone effects.

Pharmacokinetics.

Absorption.

After oral administration of progesterone as a micronised soft gelatin capsule formulation, maximum serum concentrations were attained within 3 hours. The absolute bioavailability of micronised progesterone is not known. A bioavailability of 8.6% for the oral capsule of progesterone relative to the intramuscular dosage is suggested. Table 1 summarizes the mean pharmacokinetic parameters in postmenopausal women after five oral daily doses of Prometrium capsules 100 mg as a micronised soft gelatin capsule formulation.
Serum progesterone concentrations appeared linear and dose proportional following multiple dose administration of Prometrium capsules 100 mg over the dose range 100 mg per day to 300 mg per day in postmenopausal women. Although doses greater than 300 mg per day were not studied in females, serum concentrations from a study in male volunteers appeared linear and dose proportional between 100 mg per day and 400 mg per day. The pharmacokinetic parameters in male volunteers were generally consistent with those seen in postmenopausal women.
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.
Although there were interindividual variations, the individual pharmacokinetic characteristics were maintained over several months, indicating predictable responses to the drug.

Distribution.

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).

Clinical Trials

Adjunctive use with an oestrogen in postmenopausal women with an intact uterus (for hormone replacement therapy [HRT]).

Three company sponsored studies have been conducted to investigate efficacy of Prometrium during hormone replacement therapy.
1. Study Lorrain 1994 was an open label, single centre, randomised, parallel group, prospective trial that evaluated and compared the efficacy, safety and tolerance of Prometrium and medroxyprogesterone acetate (MPA) in menopausal women receiving transdermal oestradiol for a period of at least 13 cycles.
This clinical study was an open label, single centre, randomised, parallel group, prospective trial. Postmenopausal women were randomised to treatment with Prometrium 200 mg/day (two 100 mg oral tablets taken at bedtime) or MPA (Provera) 10 mg/day (one 10 mg tablet taken at bedtime). Prometrium or MPA were taken from day 14 to day 25. All women received 17-β-estradiol 0.05 mg/day patches that were applied twice weekly from day 1 to day 25.
The efficacy outcome measures assessed were bleeding patterns. A total of 40 women were randomised to receive Prometrium (n = 20) or MPA (n = 20). The incidence of amenorrheic cycles was greater in women treated with Prometrium (42/215 cycles, 19.5%) versus MPA (6/178, 3.4%). The incidence of breakthrough bleeding was similar in women treated with Prometrium (7/222, 3.2%) versus MPA (8/181, 4.4%).
Menstruation occurred earlier, was less abundant, and of shorter duration in women treated with Prometrium versus MPA (see Table 2).
In conclusion, the use of Prometrium (progesterone) for postmenopausal HRT produced more desirable bleeding patterns than MPA.
2. Study Moyer 1987 was a 5 year, open label, noncontrolled, single centre, observational study that evaluated the endometrial situation of patients who regularly used combinations of Oestrogel (E2) and Prometrium (P) for at least 5 years. The primary outcome for this study was endometrial histology in response to treatment with HRT.
This was a 5 year, open label, noncontrolled, single centre, observational study. Women were administered combinations of percutaneous oestrogen (Oestrogel) at either 1.5 mg/day or 3 mg/day on days 1 to 21 of their cycle and oral Prometrium capsules at either 200 mg/day or 300 mg/day on days 8 to 21 of their cycle for at least 5 years. Initially, women were administered Oestrogel 1.5 mg/day plus Prometrium 200 mg/day. The dose of Oestrogel was increased to 3.0 mg/day if optimal improvement in clinical menopause symptoms was not obtained within the first 6 months of treatment. The dose of Prometrium was increased to 300 mg/day if cyclic withdrawal bleeding was not occurring during the first 6 months of treatment and women preferred cyclic withdrawal bleeding.
In conclusion, Oestrogel and Prometrium resulted in favourable bleeding patterns with higher doses of Oestrogel and Prometrium resulting in a higher incidence of cyclic bleeding.
3. Study Christiansen 1985 was a single centre, double blind (1st year) then single blind (2nd year), randomised, parallel group study that compared and evaluated the efficacy and safety of percutaneous oestradiol versus placebo and calcium as prophylaxis of symptoms in early postmenopausal women.
For the oestradiol cream (Oestrogel 60 mg oestradiol per 100 g gel), 5 grams was applied topically from days 1 to 24 of the woman's cycle. The oestradiol gel, Ca2+ tablet, and matching placebos were supplied double blind.
In the 2nd year of the study, progesterone (Prometrium 100 mg oral capsules) was added to the treatment regimen for groups I and II. Women were instructed to take two Prometrium 100 mg capsules at bedtime from days 13 to 24 of their cycle. Progesterone was dispensed open label.
Enrolled women were healthy women 45 to 54 years of age who had experienced a spontaneous menopause in the previous 6 months to 3 years.
The primary outcome measures assessed were the evaluation of menopausal symptoms using the Kupperman index.
The Kupperman index was based on 11 symptoms of menopause: hot flushes, paraesthesia, insomnia, nervousness, melancholia, vertigo, fatigue, arthralgias/ myalgias, headaches, palpitations and formication. In the calculation of this index, some of the symptoms are weighted: hot flushes (x4), paraesthesias (x2), insomnia (x2), and nervousness (x2). The maximum score was 51 and the severity of symptoms was scored on a scale of 0 (none) to 3 (severe).
Overall, the median percent decrease in Kupperman score from baseline was greatest for groups I and II (see Table 3). After 3 months of treatment, there were statistically significant differences among groups in the median percent decrease from baseline. Both groups I and II had significantly greater improvements in their scores compared with groups III and IV (P = 0.0033). Significantly greater improvements were also recorded at 18 months for groups I and II compared with groups III and IV (P = 0.0377). However, there were no statistically significant differences among groups at 6, 9, 12, 15, 21 or 24 months. The addition of progesterone to the treatment regimen in groups I and II at 12 months did not appear to have any significant effect on the menopausal symptoms.
In conclusion, percutaneous Oestrogel is effective and safe in the prophylaxis of menopausal symptoms. The addition of calcium or progesterone does not have any appreciable effect on these symptoms.
Findings from the efficacy analysis provided strong evidence for the use of oral progesterone in combination with oestrogen for HRT in postmenopausal women with an intact uterus. These findings were based primarily on the pivotal company sponsored studies showing favourable bleeding patterns with Prometrium and a Cochrane review and meta-analysis of data from placebo controlled RCTs1, which was considered to be of high quality. Findings from the meta-analysis of 6 placebo controlled RCTs showed a significant reduction in the frequency and severity of hot flushes in perimenopausal or postmenopausal women receiving oral oestrogen in combination with progestogens compared with placebo for at least 3 months. The most recent guidelines from the British Menopause Society2 recommend that transdermal preparations should be used in high risk women who require HRT and that micronised progesterone or dydrogesterone are suitable options when a progestogen is required. Overall, the aim is to replace hormones to as close to physiological levels as possible.
The body of evidence from national guidelines from Australia3, Canada4, and the US5, and international guidelines6 suggest that HRT is the most effective treatment for controlling menstrual cycles and for reducing vasomotor symptoms, including hot flushes and night sweats, in postmenopausal women with an intact uterus.

Menstrual irregularities due to ovulation disorders or anovulation.

Study Simon 1988[52, 53] was a single centre, double blind, placebo controlled phase III study that assessed the efficacy and safety of Prometrium 200 and 300 mg with placebo in the initiation of withdrawal bleedings in nonmenopausal patients with secondary amenorrhoea.
The aim of this clinical study was to compare the efficacy of Prometrium with placebo for the initiation of withdrawal bleeding in women with secondary amenorrhoea.
The primary outcome was the initiation of withdrawal bleeding. Withdrawal bleeding was defined as any bleeding or blood stained discharge from the vagina during the withdrawal interval. The withdrawal interval was defined as the time from the beginning of treatment up to, and including, 1 week after the final dose. The number of days until bleeding occurred was determined by computing the number of days between the first dose of medication and the initiation of withdrawal bleeding. The maximum number of days allowed to be considered as a positive response was 16 days.
The percentage of women experiencing withdrawal bleeding in the 3 groups was 53% (10/19) in the Prometrium 200 mg group, 90% (18/20) in the Prometrium 300 mg group and 24% (5/21) in the placebo group (see Table 4). The differences between the Prometrium 300 mg group and Prometrium 200 mg group, and the Prometrium 300 mg group and placebo, were both statistically significant. The difference between the Prometrium 200 mg group and placebo was not statistically significant. However, when the analysis was expanded to include all women who had bleeding within 30 days of starting treatment, there was a significant difference between the Prometrium 200 mg group and placebo.
In conclusion, both Prometrium 200 mg and 300 mg were effective in the initiation of withdrawal bleeding in women with secondary amenorrhoea.
One literature study (a Cochrane systematic review) was retrieved from the systematic search. Findings from this systematic review of the literature, published in 2012[88], indicated that no high quality evidence currently exists for this indication and that further research is needed to establish the role of progesterone in the management of menstrual irregularities. No RCTs are available to provide strong evidence of a beneficial effect of progesterone in the treatment of menstrual irregularities, primarily due to ovulation disorders and anovulation. However, anecdotal information and limited clinical data do suggest that progesterone does have a beneficial effect when used to treat menstrual irregularities. Progestogens, including Prometrium, are widely used, alone or in combination with oestrogens, and are authorised in many countries for this indication. The regimen, dose and type of progestogen used vary widely, with little consensus about the optimum treatment approach. The weakness in the data does not preclude treatment where, in the judgment of the physician, progesterone, alone or in combination with oestrogen, could help with symptomatic control.

Indications

Prometrium 100 and 200 mg soft capsules are indicated for the following.

Treatment of menstrual irregularities.

In women with menstrual abnormalities or secondary amenorrhoea due to normogonadotrophic amenorrhoea (see Dosage and Administration).

Hormone replacement therapy.

Hormone replacement therapy, adjunctive use with an oestrogen in postmenopausal women with an intact uterus.

Contraindications

Prometrium 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 disorders.
Thrombophlebitis.
Cerebral haemorrhage.
Porphyria.

Precautions

The use of oral Prometrium is not a treatment for premature labour.
During pregnancy, progesterone should only be used during the first three months and only by the vaginal route. Prescription of progesterone beyond the first trimester of pregnancy may reveal gravidic cholestasis.
Prometrium is not suitable for use as a contraceptive.
If unexplained, sudden or gradual, partial or complete loss of vision, proptosis or diplopia, papilloedema, retinal vascular lesions or migraine occur during therapy, the drug should be discontinued and appropriate diagnostic and therapeutic measures instituted.
Prometrium is intended to be coprescribed with an oestrogen product as HRT. Epidemiological evidence suggests that the use of HRT is associated with an increased risk of developing deep vein thrombosis (DVT) or pulmonary embolism. The prescribing information for the coprescribed oestrogen product should be referred to for information about the risks of venous thromboembolism.
There is suggestive evidence of a small increased risk of breast cancer with oestrogen replacement therapy. It is not known whether concurrent progesterone influences the risk of cancer in postmenopausal women taking hormone replacement therapy. The prescribing information for the coprescribed oestrogen product should be referred to for information about the risks of breast cancer.
Prior to taking hormone replacement therapy (and at regular intervals thereafter) each woman should be assessed. A personal and family medical history should be taken and physical examination should be guided by this and by the contraindications and warnings for this product. Prometrium should not be taken with food and should be taken at bedtime. Concomitant food ingestion increases the bioavailability of Prometrium.
Prometrium 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.
Clinical examination of the breasts and pelvic examination should be performed where clinically indicated rather than as a routine procedure. Women should be encouraged to participate in the national breast cancer screening programme (mammography) and the national cervical cancer screening programme (cervical cytology) as appropriate for their age. Breast awareness should also be encouraged and women advised to report any changes in their breasts to their doctor or nurse.
Prometrium contains soya lecithin which may cause hypersensitivity reactions (urticaria and anaphylactic shock).

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.

Use in pregnancy.

(Category A)
Prometrium should be ceased as soon as pregnancy is confirmed unless otherwise prescribed by the treating physician. Progesterone crosses the placenta. Data from clinical studies and postmarket adverse event reporting has not found an association between the use of progesterone in human pregnancy and fetal malformations. Male and female genital abnormalities (hypospadias and virilisation) have been observed in fetuses of animals treated with progesterone during gestation.

Use in lactation.

Detectable amounts of progesterone enter the breast milk. There are no indications for HRT during lactation.

Paediatric use.

There is no experience in children as there is no relevant indication for use of Prometrium in children.

Use in the elderly.

No clinical data have been collected in patients over age of 65.

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.

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 not been tested for carcinogenicity in animals by the oral route of administration. 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.

Interactions

Progesterone is metabolised primarily by the liver. Caution should be taken with drugs that are P450 enzyme inducers and inhibitors.
Metabolism of Prometrium 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.
Prometrium may interfere with the effects of bromocriptine and may raise the plasma concentration of ciclosporin.
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.

Effect on laboratory tests.

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

Adverse Effects

Somnolence or transient dizziness may occur 1 to 3 hours after intake of the drug. Bedtime dosing and reduction of the dose may reduce these effects.
Shortening of the cycle or breakthrough bleeding may occur. If this occurs, the dose of Prometrium can be reduced and taken at bedtime from day 1 to day 26 of each therapeutic cycle.
Acne, urticaria, rashes, fluid retention, weight changes, gastrointestinal disturbances, changes in libido, breast discomfort, premenstrual symptoms, menstrual disturbances; also chloasma, depression, pyrexia, insomnia, alopecia, hirsutism; rarely jaundice.
Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among nonusers.
The following effects listed by system organ class have been reported for Prometrium administered orally.
Common adverse effects: ≥ 1/100, < 1/10; uncommon adverse effects: ≥ 1/1000, < 1/100; rare adverse effects: ≥ 1/10000, < 1/1000; very rare adverse effects: ≤ 1/10,000.

Reproductive system and breast disorders.

Common: altered periods, amenorrhoea, intercurrent bleeding. Uncommon: mastodynia.

Nervous system disorders.

Common: headache. Uncommon: drowsiness, fleeting dizzy sensations. Very rare: depression.

Gastrointestinal disorders.

Uncommon: vomiting, diarrhoea, constipation. Rare: nausea.

Hepatobiliary disorders.

Uncommon: cholestatic jaundice.

Immune system disorders.

Very rare: urticaria.

Skin and subcutaneous tissue disorders.

Uncommon: pruritus, acne. Very rare: chloasma.
Drowsiness and/or fleeting dizzy sensations are seen particularly with concomitant hypoestrogenism. These effects disappear immediately without compromising the benefit of treatment when doses are reduced or oestrogenization is increased.
If the treatment sequence is started too early in the month, particularly before the 15th day of the cycle, the cycle may be shortened or intercurrent bleeding may occur.
Changes in periods, amenorrhoea or intercurrent bleeding have been observed and associated with the use of progesterones in general.

Dosage and Administration

In women receiving oestrogen replacement therapy with intact uterus, the adjunctive use of progesterone at a dose of 200 mg daily at bedtime should be adminsitered for twelve days in the last half of each therapeutic cycle (beginning on day 15 of the cycle and ending on day 26). Withdrawal bleeding may occur in the following week. Alternatively 100 mg can be given at bedtime from day 1 to day 25 of each therapeutic cycle, withdrawal bleeding being less with this treatment schedule.
In women with secondary amenorrhoea, the treatment may be given as a single daily dose of 400 mg (2 capsules 200 mg) at bedtime for 10 days. Prior to use for this indication, other causes of secondary amenorrhoea such as outflow obstruction, pregnancy, prolactinoma, thyroid disorders, pituitary and hypothalamic disorders should be excluded.
The standard daily dosage regimen is 200 to 300 mg of progesterone taken in one or two doses (i.e. 200 mg in the evening before retiring and another 100 mg in the morning, if needed). In menstrual irregularities due to ovulation disorders or anovulation, the treatment is administered over 10 days per menstrual cycle, usually from cycle days 17 to 26 inclusive.

Children.

Not applicable.

Elderly.

As for adults.

Method of administration.

Oral. Prometrium should not be taken with food.

Overdosage

Symptoms of overdosage may include somnolence, dizziness, euphoria or dysmenorrhoea. Treatment is observation and, if necessary, symptomatic and supportive measures should be provided.
The usual dosage may be excessive in some people because of persistence or recurrence of unstable endogenous progesterone secretion, and some people with particular sensitivity to progesterone or excessively low concomitant blood oestradiol concentrations. In these situations, the dosage should be reduced or the progesterone should be administered in the evening at bedtime, 10 days per cycle, if drowsiness or fleeting dizziness occurs.
Treatment should be started later in the cycle (such as on day 19 instead of day 17) if the cycle is shortened or spotting occurs.
Check that oestradiol concentration is sufficient in the perimenopausal period and in hormone replacement therapy in postmenopause.
In case of overdose, immediately contact the Poisons Information Centre (in Australia, call 131 126) for advice.

Presentation

Soft capsules (slightly yellow, contains whitish oily suspension), 100 mg (round): 14's*, 15's*, 28's*, 30's, 56's*, 84's*, 90's* (PVC/ aluminium blisters, carton); 200 mg* (ovoid): 7's, 14's, 15's, 21's, 28's, 30's, 42's, 45's, 56's, 84's, 90's (PVC/ aluminium blisters, carton).
*Not currently marketed in Australia.

Storage

Store below 30°C.
Do not refrigerate.
Store in the original container.

References

1. Maclennan et al, 2004
2. Panay et al, 2013
3. RANZCOG, 2011
4. Reid et al, 2009
5. NAMS, 2012
6. de Villiers et al, Mauritius 2013, de Villiers et al, 2013

Poison Schedule

S4.