Consumer medicine information

Endometrin Pessaries

Progesterone

BRAND INFORMATION

Brand name

Endometrin

Active ingredient

Progesterone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Endometrin Pessaries.

What is in this leaflet

This leaflet answers some common questions about Endometrin Pessaries.

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 using Endometrin against the benefits they expect it will have for you.

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

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

What Endometrin is used for

Endometrin is provided as a pessary (or vaginal tablet) that contains the natural female hormone, progesterone.

Endometrin is for women who need extra progesterone while undergoing treatment in an Assisted Reproductive Technology (ART) programme (e.g. IVF).

Progesterone acts on the lining of the uterus (womb) and it helps you to become and to stay pregnant when you are treated for infertility.

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

Endometrin is available only with a doctor's prescription.

This medicine is not addictive.

Before you use Endometrin

When you must not use it

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

  • unusual vaginal bleeding that has not been evaluated by your doctor
  • missed abortion or ectopic pregnancy (pregnancy outside of the womb)
  • severe liver problems
  • known or suspected cancer of the breast or genital tract
  • blood clots in the legs, lungs, eyes or elsewhere in the body
  • porphyria disorder (a blood disease).

Do not use Endometrin if you are breast-feeding. If you take this medicine after the expiry date has passed, it may not work.

Do not use Endometrin after the expiry date on the pack has passed.

Do not use Endometrin if the packaging is torn or shows signs of tampering or the product does not look quite right. If it has expired or is damaged, return it to your pharmacist or doctor for disposal.

If you are not sure whether you should start using Endometrin talk to your doctor.

Before you start to use it

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
  • asthma
  • heart, liver or kidney disease
  • diabetes
  • history of depression.

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

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:

  • rifampicin
  • carbamazepine
  • St John's Wort (herbal product)
  • ketoconazole.

Endometrin should not be used at the same time as other vaginal preparations. Your doctor or pharmacist has more information on medicines to be careful with or avoid while using Endometrin.

How to use Endometrin

How much to use

Your doctor or pharmacist will tell you how many tablets you need to use each day. The usual dosage is one 100 mg tablet placed directly into the vagina three times daily starting on the day of egg retrieval.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

Endometrin tablets are intended to be placed directly into the vagina. An applicator is provided in the pack to help administer the tablets.

Follow the directions on how to administer the tablet below:

  • wash your hands thoroughly with soap and water
  • unwrap the applicator and remove one vaginal tablet from the blister
  • put one tablet in the space provided at the end of the applicator. The tablet should fit securely and not fall out
  • the applicator with the tablet may be inserted into the vagina while you are standing, sitting, or when lying on your back with your knees bent. Gently insert the thin end of the applicator well into the vagina
  • push the plunger to release the tablet
  • remove the applicator and rinse it thoroughly in warm running water, wipe dry with a soft tissue and keep the applicator for subsequent use.

The directions on how to administer the tablet are also provided with each pack of Endometrin.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How long to use it

The use of Endometrin may be continued for up to 10 weeks if pregnancy is confirmed (12 week of gestation).

If you forget to use it

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

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

Do not use 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 use your medicine, ask your pharmacist for some hints.

If you use 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 used too much Endometrin. Do this even if there are no signs of discomfort or poisoning.

While you are using Endometrin

Things you must do

Tell any other doctors or pharmacists who are treating you that you are using Endometrin.

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

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 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 Endometrin to anyone else, even if they have the same condition as you.

Do not use Endometrin to treat any other complaints unless your doctor has told you to.

Do not stop using Endometrin 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 Endometrin affects you. Some people may experience drowsiness or dizziness. Make sure you know how you react to Endometrin 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 using Endometrin. Endometrin helps most people with low progesterone levels, 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
  • vaginal disorders (such as discomfort, burning sensation, discharge, dryness and bleeding)
  • uterine cramping
  • abdominal pain or bloating (swelling)
  • nausea.

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:

  • dizziness
  • insomnia
  • diarrhoea
  • constipation
  • urticaria (allergic rash)
  • rash
  • vaginal disorders (e.g. vaginal discomfort, burning sensation, discharge, dryness and bleeding)
  • fungal infections in the vagina (e.g. vaginal thrush)
  • breast disorders (e.g. breast pain, breast swelling and breast tenderness)
  • itching in the genital area
  • swelling of the limbs.

The above list includes serious side effects which may require medical attention. Serious side effects are 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 this list of possible side effects. You may not experience any of them.

After using Endometrin

Storage

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

Keep this medicine in a cool dry place where the temperature stays below 25°C.

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 using 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

Endometrin Pessaries are white to off-white, convex and oblong tablets with the inscriptions "FPI" on one side and "100" on the other side. Endometrin Pessaries are supplied in blister strips packaged in an outer carton. Each carton contains 21 tablets and one vaginal applicator.

Ingredients

Active ingredient:

  • progesterone.

Inactive ingredients:

  • colloidal anhydrous silica
  • lactose monohydrate
  • pregelatinised maize starch
  • povidone
  • adipic acid
  • sodium bicarbonate
  • sodium lauryl sulphate
  • magnesium stearate.

Sponsor

Endometrin Pessaries are supplied in Australia by:

Ferring Pharmaceuticals Pty Ltd
Suite 2, Level 1, Building 1,
20 Bridge Street
Pymble, NSW 2073

This leaflet was prepared in September 2019.

Endometrin Pessaries 100 mg
AUST R 189948

DOCS#30117v2A

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Endometrin

Active ingredient

Progesterone

Schedule

S4

 

1 Name of Medicine

Endometrin Pessaries progesterone 100 mg vaginal tablets.

6.7 Physicochemical Properties

The chemical name for progesterone is pregn-4-ene-3,20-dione.
It has an empirical formula of C21H30O2 and a molecular weight of 314.5.

Chemical structure.

The structural formula of progesterone is:

CAS number.

57-83-0.

2 Qualitative and Quantitative Composition

Endometrin Pessaries (vaginal tablets) contain 100 mg progesterone (micronised) and also the following excipients: colloidal anhydrous silica, lactose monohydrate, pregelatinised maize starch, povidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate.

3 Pharmaceutical Form

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

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate oestrogen, progesterone transforms a proliferative endometrium into a secretory endometrium. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain the pregnancy.

Clinical trials.

A multicentre, randomised, open label phase III study was conducted to determine the efficacy of Endometrin Pessaries 100 mg BID and 100 mg TID administered vaginally in women undergoing IVF and to demonstrate noninferiority of Endometrin versus Crinone 8% vaginal gel (90 mg) once daily (QD).
The primary efficacy variable was ongoing pregnancy following one treatment cycle in the efficacy population. Ongoing pregnancy was defined as identification of fetal heart movement at approximately 6 weeks of gestation. The primary analysis was performed to determine if the ongoing pregnancy rate for each dose of Endometrin was noninferior to the comparator Crinone 8% (90 mg). To declare noninferiority, the lower bound of the 95% confidence interval should exclude a difference greater than 10% in favour of the comparator. Thus, the trial investigated the relative efficacy of Endometrin versus the active comparator Crinone, and used -10% as noninferiority limit based on clinical trials with gonadotrophins used for controlled ovarian stimulation. The absolute efficacy of Endometrin has not been investigated, as trials versus placebo (inactive) have not been conducted. To adjust for multiple comparisons, Endometrin 100 mg TID versus Crinone was considered the primary comparison. If the lower bound of the 95% confidence interval excluded a difference greater than 10% in favour of Crinone, then the noninferiority of Endometrin 100 mg BID versus Crinone was assessed.
A total of 1211 patients undergoing IVF were randomised to receive either Endometrin 100 mg BID (n = 404), Endometrin 100 mg TID (n = 404) or Crinone 8% gel (90 mg) QD (n = 403). Subjects ranged in age from 19 to 42 years. The study drug was initiated on the day after oocyte retrieval and was continued for a total duration of approximately 10 weeks if the patient conceived.
The patient population in this study was also prestratified and randomised according to age (< 35, 35-37, 38-40, 41-42 years). Women up to 35 years of age constituted 61% (N = 737) of the trial population and the majority had FSH levels < 10 IU/L (N = 1047/1193, 88%). The study was powered to demonstrate noninferiority overall for the entire trial population, not for each of the age groups.
The ongoing pregnancy rates in the study were as follows overall, and per age strata. (See Table 2.)
Endometrin 100 mg TID met the noninferiority criterion relative to Crinone 8%, as Endometrin TID was well within the 10% lower bound to demonstrate noninferiority in ongoing pregnancy rate to Crinone 8%. Endometrin BID was just above the 10% lower bound in ongoing pregnancy rate.
Ongoing pregnancy and live birth rates following 10 week luteal support with Endometrin Pessaries are available from the phase III clinical trial. Endometrin 100 mg BID (N = 392) was associated with an ongoing pregnancy rate of 39.8% (95% CI 34.9; 44.9) and a live birth rate of 36.0% (95% CI 31.2; 40.9) in patients who had an embryo transfer. For Endometrin 100 mg TID (N = 390), the ongoing pregnancy and live birth rates in patients with embryo transfer were 43.8% (95% CI 38.9; 48.9) and 39.5% (95% CI 34.6; 44.5), respectively.

5.2 Pharmacokinetic Properties

Absorption.

Progesterone serum concentrations increased following the administration of the Endometrin vaginal tablets in 12 healthy premenopausal females. On single dosing, the mean Cmax of endogenous and exogenous progesterone was 17.0 nanogram/mL in the Endometrin twice daily (BID) group and 19.8 nanogram/mL in the Endometrin three times daily (TID) group.
On multiple dosing, steady state concentrations were attained within approximately 1 day after initiation of treatment with Endometrin. Both Endometrin regimens provided average serum concentrations of progesterone exceeding 10 nanogram/mL on day 5. The pharmacokinetic results are summarised in Table 3.

Distribution.

Progesterone is approximately 96% to 99% bound to serum proteins, primarily to serum albumin and corticosteroid binding globulin.

Metabolism.

Progesterone is metabolised primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites that are excreted in the bile may be deconjugated and may be further metabolised in the gut via reduction, dehydroxylation, and epimerization.

Excretion.

Progesterone undergoes renal and biliary elimination. Following injection of labelled progesterone, 50-60% of the excretion of metabolites occurs via the kidney; approximately 10% occurs via the bile and faeces. Overall recovery of the labelled material accounts for 70% of an administered dose. Only a small portion of unchanged progesterone is excreted in the bile.

5.3 Preclinical Safety Data

Genotoxicity.

Progesterone did not induce dominant lethal mutations in mice or chromosomal aberrations in the bone marrow of rats in vivo. It did not induce chromosomal aberrations or sister chromatid exchanges in cultured human cells nor chromosomal aberrations or DNA strand breaks in rodent cells. 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. The exposure to women is relatively short and use of progesterone as part of an assisted reproduction regimen (ART) is regarded as replacement therapy.

4 Clinical Particulars

4.1 Therapeutic Indications

Endometrin Pessaries are indicated for luteal support as part of an assisted reproductive technology (ART) treatment programme for infertile women.

4.3 Contraindications

Endometrin Pessaries should not be used in individuals with any of the following conditions:
Hypersensitivity to progesterone or to any of the excipients.
Undiagnosed vaginal bleeding.
Known missed abortion or ectopic pregnancy.
Severe hepatic dysfunction or disease.
Known or suspected breast or genital tract cancer.
Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.
Porphyria.

4.4 Special Warnings and Precautions for Use

Endometrin Pessaries should be discontinued if any of the following conditions are suspected: myocardial infarction, cerebrovascular disorders, arterial or venous thromboembolism (venous thromboembolism or pulmonary embolism), thrombophlebitis, or retinal thrombosis.
Use with caution in patients with mild to moderate hepatic dysfunction.
Patients with a history of depression need to be closely observed. Consider discontinuation if symptoms worsen.
Because progesterone may cause some degree of fluid retention, conditions that might be influenced by this factor (e.g. epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation.
A decrease in insulin sensitivity and thereby in glucose tolerance has been observed in a small number of patients on oestrogen-progestogen combination drugs. The mechanism of this decrease is not known. For this reason, diabetic patients should be carefully observed while receiving progesterone therapy.
Sex steroid use may also increase the risk of retinal vascular lesions. To prevent these latter complications, caution is to be taken in users > 35 years, in smokers, and in those with risk factors for atherosclerosis. Use should be terminated in the case of transient ischemic events, appearance of sudden severe headaches, or vision impairments related to papillary oedema or retinal haemorrhage.
Abrupt discontinuation of progesterone dosing may cause increased anxiety, moodiness, and increased sensibility to seizures.
Before starting treatment with Endometrin, the patient and her partner should be assessed by a doctor for causes of infertility.

Use in special populations.

There is no experience with the use of Endometrin in patients with impaired liver or renal function.

Use in the elderly.

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

Paediatric use.

There is no relevant use of Endometrin in the paediatric population for the indication.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs known to induce the hepatic cytochrome P450 3A4 system (such as rifampicin, carbamazepine and also herbal products containing St. John's wort (Hypericum perforatum)) may increase the elimination rate and thereby decrease the bioavailability of progesterone.
Ketoconazole and other inhibitors of cytochrome P450 3A4 may increase the bioavailability of progesterone.
The effect of concomitant vaginal products on the exposure of progesterone from Endometrin Pessaries has not been assessed. Endometrin is not recommended for use with other vaginal products (such as antifungal products) as this may alter progesterone release and absorption from the vaginal tablet.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Endometrin Pessaries are only indicated during the first trimester of pregnancy for use as part of an assisted reproduction (ART) regimen. The effect of Endometrin on fertility has not been evaluated in animals.
(Category A)
There is yet limited and inconclusive data on the risk of congenital anomalies, including genital abnormalities in male or female infants, following intrauterine exposure during pregnancy.
In the pivotal trial, the rate of foetal anomalies following 10 week exposure to Endometrin 100 mg TID was 4.5% in the Endometrin TID group, a total of 7 cases of foetal anomalies (i.e. oesophageal fistula, underdeveloped right ear with hypospadias, small aorta/ valvular regurgitation/ deviated septum, hand deformity, cleft palate/ cleft lip, hydrocephalus and holoprosencephaly/ proboscis/ polydactylia) were seen in 404 patients. The rate of foetal anomalies observed during the clinical trial is comparable with the event rate described in the general population, although the total exposure is too low to allow conclusions to be drawn.
During the conduct of the pivotal clinical trial, the number of spontaneous abortions and ectopic pregnancies associated with the use of Endometrin 100 mg TID were 5.4% and 1%, respectively.
Detectable amounts of progesterone have been identified in the milk of mothers. Therefore, Endometrin should not be used during lactation.

4.8 Adverse Effects (Undesirable Effects)

The most frequently reported adverse drug reactions during treatment with Endometrin Pessaries in IVF patients during clinical trials are headache, vulvovaginal disorders and uterine spasm, reported in 1.5%, 1.5% and 1.4% subjects, respectively. The table below (Table 1) displays the main adverse drug reactions in women treated with Endometrin in the clinical trial distributed by system organ classes (SOCs) and frequency.

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.

4.2 Dose and Method of Administration

The dose of Endometrin Pessaries is 100 mg administered vaginally three times daily starting at oocyte retrieval and continuing for up to 10 weeks total duration (or 12 weeks of gestation).
Endometrin administered into the vagina BID and TID dosing have both been shown to be efficacious. However specific populations may derive greater benefits from BID or TID dosing regimen and the clinician can tailor treatment to the patient. For women < 35 years of age and those patients with adequate ovarian reserve, Endometrin BID would be the appropriate dose. For patients aged 35 and older and those with diminished ovarian reserve, TID dosing would be the preferred regimen. Serum progesterone levels may be measured 7 days postfertilisation and used to guide therapy.
Endometrin is to be placed directly into the vagina by the applicator provided.
1. Unwrap the applicator.
2. Put one tablet in the space provided at the end of the applicator. The tablet should fit securely and not fall out.
3. The applicator with the tablet may be inserted into the vagina while you are standing, sitting or when lying on your back with your knees bent. Gently insert the thin end of the applicator well into the vagina.
4. Push the plunger to release the tablet.
5. Remove the applicator and rinse it thoroughly in warm running water, wipe dry with a soft tissue and keep the applicator for subsequent use.

4.7 Effects on Ability to Drive and Use Machines

Endometrin has minor or moderate influence on the ability to drive and use machines. Progesterone may cause drowsiness and/or dizziness; therefore caution is advised in drivers and users of machines.

4.9 Overdose

High doses of progesterone may cause drowsiness.
Treatment of overdose consists of discontinuation of Endometrin Pessaries together with institution of appropriate symptomatic and supportive care.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

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 Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Endometrin Pessaries containing 100 mg progesterone; white to off-white, convex and oblong tablets with the inscriptions "FPI" on one side and "100" on the other side. Nominal size approximately 22 mm x 13 mm. Supplied in alu/alu blisters packaged in an outer carton. Each carton contains 21 vaginal tablets with 1 vaginal applicator.

6.6 Special Precautions for Disposal

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

Summary Table of Changes