Consumer medicine information

Menopur

Menopausal gonadotrophin, human

BRAND INFORMATION

Brand name

Menopur

Active ingredient

Menopausal gonadotrophin, human

Schedule

SUMMARY CMI

MENOPUR^®

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 MENOPUR?

MENOPUR is used to treat infertility (reproduction related conditions) in women. It contains the active ingredient human menopausal gonadotrophin. For more information, see Section 1. Why am I using MENOPUR? in the full CMI.

2. What should I know before I use MENOPUR?

Do not use MENOPUR if you have ever had an allergic reaction to human menopausal gonadotrophin, gonadotrophins, or to any of the ingredients listed at the end of the CMI, see Section 7. Product details.
There are several circumstances in which a person should not use this medicine or may need to use it with caution. It is important to understand if any of these apply to you before using MENOPUR.
Talk to your doctor if you have any other medical conditions or take any other medicines.
For more information, see Section 2. What should I know before I use MENOPUR? in the full CMI.

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 MENOPUR and affect how it works. For more information, see Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use MENOPUR?

You should only use MENOPUR under the supervision of a doctor experienced in the treatment of infertility.
Always use this medicine exactly as your doctor has told you. You should check with your doctor if you are unsure. Your doctor will determine your dose of MENOPUR depending on your condition.
Before using MENOPUR, you must be educated on how to prepare the injection solution and how to perform injections. Your first injection must be supervised by a trained health practitioner.

More instructions can be found in Section 4. How do I use MENOPUR? in the full CMI and in the ‘Instructions for Use’ leaflet inside the carton.

5. What should I know while using MENOPUR?

Things you should do	Tell any doctor, dentist or pharmacist you visit that you are using MENOPUR. Be sure to keep all your doctor's appointments so your progress can be checked regularly.
Things you should not do	Do not stop using this medicine or change the dose without talking to your doctor. Do not give this medicine to anyone else even if they have the same condition as you.
Looking after your medicine	Store MENOPUR in a refrigerator (2°C to 8°C). Do not freeze. Always store MENOPUR in the original pack until it is time to use it. After mixing powder with solvent, the solution may be stored in a refrigerator for up to 28 days.

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

6. Are there any side effects?

All medicines can have side effects. Most of them are minor and temporary but some may need medical attention.
Tell your doctor if you experience any side effects.

Common side effects include skin reactions at the site where MENOPUR has been injected, such as redness, pain and swelling.

Pain and/or swelling in the abdomen or pelvic region, nausea, vomiting, diarrhoea, weight gain, having difficulty breathing and/or reduced urination may be a sign of too much activity in the ovaries and may require urgent medical attention in hospital. For more information, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

MENOPUR^® Powder and solvent for solution for injection

Active ingredient: human menopausal gonadotrophin

Consumer Medicine Information (CMI)

This leaflet provides important information about using MENOPUR. 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 MENOPUR.

Where to find information in this leaflet:

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

1. Why am I using MENOPUR?

MENOPUR is used to treat infertility (reproduction related conditions) in women. It belongs to a class of medicines called gonadotrophins.

MENOPUR contains the active ingredient highly purified human menopausal gonadotrophin (hMG) obtained from the urine of post-menopausal women. hMG is a mixture of hormones found naturally in humans, with follicle stimulating hormone (FSH) activity and luteinising hormone (LH) activity.

MENOPUR is used to stimulate the ovaries to grow and develop egg sacs (‘follicles’).

MENOPUR is used to stimulate the follicles in women undergoing Assisted Reproductive Technology (ART) procedures to help them become pregnant. ART procedures include IVF/ET (in vitro fertilisation/embryo transfer), GIFT (gamete intrafallopian transfer) and ICSI (intracytoplasmic sperm injection).

MENOPUR is also used in women who are not ovulating (not releasing eggs) naturally and who have not responded to another medicine called clomiphene citrate.

2. What should I know before I use MENOPUR?

Warnings

Do not use MENOPUR if:

you are allergic to human menopausal gonadotrophin, gonadotrophins, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
you are pregnant or breastfeeding
you have cancer of the uterus (womb), ovaries, or breasts
you have a tumour of the pituitary gland or hypothalamus
you have enlarged ovaries or cysts on your ovaries not caused by polycystic ovarian disease
you have bleeding from the vagina where the cause is not known
your ovaries have failed
you have malformations of the sexual organs, which make a normal pregnancy impossible
you have fibroids, or tumours, of the uterus (womb), which make a normal pregnancy impossible.

Do not use MENOPUR if the expiry date printed on the pack has passed.

Tell your doctor if you:

have or have had any other medical conditions, especially the following:
- adrenal problems
- thyroid problems
- high prolactin levels in the blood
- blood clots, a history of blood clots, or any condition that puts you at risk of blood clots
- polycystic ovarian syndrome (PCOS)
- ovarian hyperstimulation syndrome (OHSS)
- fallopian tube disease
- kidney or liver disease.
take any medicines for any other condition.

Your doctor will assess you and your partner's fertility. This may include tests for other medical conditions, including medical conditions which may interfere with your ability to become pregnant. If necessary, other medical conditions may be treated before starting infertility treatments, including the use of MENOPUR.

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?

Pregnancy and breastfeeding

Do not use MENOPUR if you are pregnant or breastfeeding.

It may affect your developing baby if you use it during pregnancy. Talk to your doctor immediately if you become pregnant while using MENOPUR.

Pregnancy risks

The risk of a pregnancy outside of the womb (ectopic pregnancy) may be higher after assisted reproduction than if you conceive naturally. If you have a history of tubal disease, you have an increased risk of ectopic pregnancy.
Compared to natural conception, the frequency of pregnancy loss is higher in patients undergoing fertility treatments.
Multiple pregnancy, more than one baby at a time, carries greater risks for mothers and babies. In patients undergoing ART procedures, the risk of multiple pregnancy is related to the number of embryos replaced, their quality and your age. Your doctor will monitor your response to treatment to minimise the chance of multiple pregnancies.
There may be a slightly increased risk of birth defects in women using assisted reproductive technologies. This may be due to increased maternal age, genetic factors, multiple pregnancies or the procedures.

Some women who have been given multiple medicines for infertility treatment have developed tumours in the ovaries and other reproductive organs. It is not yet known if treatment with hormones like MENOPUR causes these problems.

Ovarian hyperstimulation syndrome (OHSS)

Some people have an exaggerated response to hormones used in ART, including MENOPUR. This may lead to ovarian hyperstimulation syndrome (OHSS). This is when your follicles develop too much causing your ovaries to swell and become painful.

Talk to your doctor if you have:

abdominal pain, discomfort or swelling
nausea
vomiting
diarrhoea
weight gain
difficulty in breathing
decreased urination.

Blood clots

Tell your doctor if you or a family member have or have had blood clots or signs of blood clots (e.g. pain, warmth, redness, numbness or tingling in the arm or leg).

Blood clots are more likely to form inside your blood vessels when you are pregnant. This is more likely if you have had treatment to help you become pregnant and:

you are overweight (BMI > 30 kg/m²)
you have a condition that increases your risk of having blood clots ‘thrombophilia’
you or someone in your family (blood relative) has had blood clots.

3. What if I am taking other medicines?

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

Clomiphene citrate is another medicine used in the treatment of infertility. If MENOPUR is used at the same time as clomiphene citrate, the effect on the ovaries may be increased.

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

4. How do I use MENOPUR?

Treatment with MENOPUR should be started under the supervision of a specialist doctor experienced in the treatment of infertility.

How much to use

Always use this medicine exactly as your doctor has told you. You should check with your doctor if you are unsure.

The dose of MENOPUR and the length of treatment will be determined by your doctor depending on your condition.

Women who are not ovulating (not releasing eggs) without treatment:

The initial dose is normally 75-150 IU daily.
Your doctor may change the dose, according to your response to the treatment, up to a maximum of 225 IU per day.
The same dose should be given for at least 7 days before the dose is changed by the doctor.
Your doctor will monitor the effect of MENOPUR treatment. The cycle of treatment should be stopped if there is no response after 4 weeks.

Women undergoing Assisted Reproductive Technology (ART):

The initial dose of MENOPUR is normally 150-225 IU.
Your doctor may change the dose, according to your response to the treatment, up to a maximum of 450 IU per day.
Normally treatment should not continue for more than 20 days.

When to use MENOPUR

Women who are not ovulating (not releasing eggs) without treatment:

Treatment should start within the first 7 days of the menstrual cycle (Day 1 is the first day of your period). Treatment should be given every day for at least 7 days.
When a good response is obtained, a single injection of another hormone called human chorionic gonadotrophin (hCG), should be given 1 day following the last MENOPUR injection. It is recommended that you have sexual intercourse on the day of the hCG injection and the day after. Alternatively, artificial insemination (injection of sperm directly into the womb) may be performed. Your doctor will closely monitor your progress for at least 2 weeks after you have received the hCG injection.
Your doctor will monitor the effect of MENOPUR treatment. Depending on your progress, your doctor may decide to stop treatment with MENOPUR and not give you the hCG injection. In this case, you will be instructed to use a barrier method of contraception (e.g. condom) or not have sexual intercourse until your next period has started.

Women undergoing Assisted Reproductive Technology (ART):

If you are also receiving treatment with a GnRH agonist (a medicine that acts like a hormone called Gonadotrophin Releasing Hormone, GnRH), MENOPUR should be started approximately 2 weeks after the start of the GnRH agonist therapy.
In patients receiving a GnRH antagonist, MENOPUR treatment should be started on day 2 or 3 of the menstrual cycle (Day 1 is the first day of your period).
Treatment should be given every day for at least 5 days.
If enough follicles have developed, you will be given a single injection of a medicine called human chorionic gonadotrophin (hCG) to stimulate the final maturation of the eggs in the follicles prior to collection and fertilisation.
Your doctor will closely monitor your progress for at least 2 weeks after you have received the hCG injection.
Your doctor will monitor the effect of MENOPUR treatment. If you have responded too strongly to MENOPUR, your doctor may decide to stop treatment with MENOPUR and not give you the hCG injection. In this case, you will be instructed to use a barrier method of contraception (e.g. condom) or not have sexual intercourse until your next period has started.

How to inject MENOPUR

MENOPUR is to be injected under the skin of your abdomen using a new area of the abdomen on each occasion.
Before using MENOPUR, you must be educated on how to prepare the injection solution and how to perform injections.
Your first injection must be supervised by a trained health practitioner.
Step-by-step instructions on how to prepare and inject MENOPUR are provided in the ‘Instructions for Use’ leaflet inside the carton.

Do not self-inject MENOPUR until you are sure of how to do it.

If you forget to use MENOPUR

If you forget an injection or are not sure what to do, contact your doctor or nurse immediately for advice.

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

If you use too much MENOPUR

MENOPUR may cause hyperstimulation of the ovaries known as ovarian hyperstimulation syndrome (OHSS). OHSS is a potentially serious complication of infertility treatment and could be fatal without proper management in hospital. The initial symptoms may consist of abdominal pain, abdominal swelling and/or nausea and vomiting.

If you think that you have used too much MENOPUR, 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.

5. What should I know while using MENOPUR?

Things you should do

Call your doctor straight away if you:

feel pain in the abdomen or pelvic region
notice swelling in the abdomen
experience nausea (feeling sick) or vomiting
develop diarrhoea
gain weight
have trouble breathing
notice you are urinating less.

Tell your doctor straight away if you notice any of the above symptoms, even if the symptoms develop some days after the last injection has been given.

This can be a sign of high levels of activity in the ovaries known as OHSS and the symptoms could become severe.

If these symptoms become severe, treatment with MENOPUR should be stopped and you should receive urgent medical attention in hospital.

Keeping to your recommended dose and careful monitoring of your treatment will reduce your chances of getting these symptoms.

You should also contact your doctor right away if you:

become pregnant
have unusual vaginal bleeding.

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

Your doctor will normally arrange for you to have ultrasound scans and do some blood and other tests from time to time to check on your progress and detect any unwanted side effects.

Tell any doctor, dentist or pharmacist you visit that you are using MENOPUR. If you are going to have surgery, tell the surgeon or anaesthetist that you are using MENOPUR.

Things you should not do

Do not stop using this medicine or change your dose without talking to your doctor.
Do not give this medicine to anyone else even if they have the same condition as you.

Driving or using machines

MENOPUR should not normally interfere with your ability to drive or operate machinery.

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

Drinking alcohol

Tell your doctor if you drink alcohol.

It is unknown how drinking alcohol will affect MENOPUR.

Looking after your medicine

Keep MENOPUR in a refrigerator at a temperature of 2°C to 8°C. Do not freeze.
Always store MENOPUR in the original pack until it is time to use it.
After mixing powder with solvent, the solution may be stored in a refrigerator at a temperature of 2°C to 8°C for up to 28 days. After 28 days, the vial containing any unused medicine should be discarded.

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.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

When to discard your medicine

Discard MENOPUR if it has been opened and reconstituted for more than 28 days.

Do not use this medicine after the expiry date.

Once you have injected MENOPUR, do not re-use the needles and syringes. Discard the used needles and syringes into an approved, puncture-resistant sharps container and keep it out of reach of children. Never put used needles and syringes into your normal household rubbish bin.

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.

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, nurse or pharmacist if you have any further questions about side effects.

Side effects

Side effects

What to do

Common side effects (affect more than 1 in 100 users):

headache
reactions at the injection site:
- redness
- itchiness
- tenderness
- pain or discomfort
- warmth or burning
- stinging
- swelling

Uncommon side effects (affect less than 1 in 100 users):

breast swelling, pain (including nipple pain), tenderness or discomfort
hot flush
dizziness
tiredness.

Rare side effects (affect less than 1 in 1,000 users):

generalised rash or itchiness
acne.

Frequency unknown:

fever
generally feeling unwell
problems with your eyes
pain in muscles or joints including back, neck and/or extremities such as the hands or feet.

These side effects are not usually serious but can become serious.
Seek immediate medical care if you have any concerns.

Serious side effects

Serious side effects

What to do

Allergic reaction (unknown frequency):

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

Ovarian hyperstimulation syndrome (OHSS):

Common signs of OHSS:
- stomach pain and/or swelling
- pelvic pain
- nausea or vomiting
- diarrhoea.
Rare complications of OHSS:
- rapid weight gain (due to fluid accumulation)
- shortness of breath
- passing less urine
- blood clots (thromboembolism)
- twisting of ovaries (ovarian torsion).

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, even if a few days have passed since your last injection, or you have stopped using MENOPUR.

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.

What MENOPUR contains

Active ingredient
(main ingredient)

human menopausal gonadotrophin

Other ingredients
(inactive ingredients)

Powder:

lactose monohydrate
polysorbate 20
dibasic sodium phosphate heptahydrate
phosphoric acid.

Solvent:

metacresol
water for injections.

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

MENOPUR 600 IU: Contains human menopausal gonadotrophin corresponding to follicle stimulating hormone (FSH) activity 600 IU and luteinising hormone (LH) activity 600 IU.

MENOPUR 1200 IU: Contains human menopausal gonadotrophin corresponding to follicle stimulating hormone (FSH) activity 1200 IU and luteinising hormone (LH) activity 1200 IU.

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

What MENOPUR looks like

MENOPUR is supplied in packs containing medicine powder (vial), solvent for reconstitution and needle for reconstitution. Disposable alcohol pads and single-use administration syringes (graduated in FSH/LH units with pre-fixed needles) are supplied separately.

Inspect the medicine vial before use to ensure that a white powder cake is visible. The cake may seem to disappear after the needle tip enters the rubber top, but you can continue with the reconstitution as long as the cake was visible on first inspection.

MENOPUR 600 IU:

The MENOPUR 600 IU pack contains one vial of powder, one pre-filled syringe with solvent for reconstitution and one needle for reconstitution (AUST R 161984).

MENOPUR 1200 IU:

The MENOPUR 1200 IU pack contains one vial of powder, two pre-filled syringes with solvent for reconstitution and one needle for reconstitution (AUST R 161985).

Who distributes MENOPUR

MENOPUR is distributed in Australia by:

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

This leaflet was prepared in April 2022

#12118-v20A

Published by MIMS June 2022

BRAND INFORMATION

Brand name

Menopur

Active ingredient

Menopausal gonadotrophin, human

Schedule

1 Name of Medicine

Human menopausal gonadotrophin (hMG).

2 Qualitative and Quantitative Composition

Menopur 600 IU (600 IU/mL after reconstitution).
Menopur 1200 IU (600 IU/mL after reconstitution).

Menopur 600 IU.

Each multidose vial with powder contains highly purified human menopausal gonadotrophin (hMG) corresponding to follicle stimulating hormone (FSH) activity 600 IU and luteinising hormone (LH) activity 600 IU.

Menopur 1200 IU.

Each multidose vial with powder contains highly purified human menopausal gonadotrophin (hMG) corresponding to follicle stimulating hormone (FSH) activity 1200 IU and luteinising hormone (LH) activity 1200 IU.

Excipient with known effect.

Not applicable.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder and solvent for solution for injection.
Appearance of powder: white to off-white lyophilisation cake.
Appearance of solvent: clear colourless solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Menopur is indicated for the treatment of infertility in the following clinical situations.
Anovulatory infertility, including polycystic ovarian disease (PCOD), in women who have been unresponsive to treatment with clomiphene citrate.
Controlled ovarian hyperstimulation to induce the development of multiple follicles for assisted reproductive technologies (ART) (e.g. in vitro fertilisation/ embryo transfer (IVF/ET), gamete intrafallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)).

4.2 Dose and Method of Administration

Treatment with Menopur should be initiated under the supervision of a physician experienced in the treatment of fertility problems.
There are great interindividual variations in the response of the ovaries to exogenous gonadotrophins. This makes it impossible to set a uniform dosage scheme. The dosage should, therefore, be adjusted individually depending on the ovarian response. Menopur can be given alone or in combination with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist. Recommendations about dosage and duration of treatment may change depending on the actual treatment protocol.

Women with anovulatory infertility (including PCOD).

The object of Menopur therapy is to develop a single Graafian follicle from which the oocyte will be liberated after the administration of human chorionic gonadotrophin (hCG).
Menopur therapy should start within the initial 7 days of the menstrual cycle. The recommended initial dose of Menopur is 75-150 IU daily, which should be maintained for at least 7 days. Based on clinical monitoring (including ovarian ultrasound alone or in combination with measurement of oestradiol levels), subsequent dosing should be adjusted according to individual patient response. Adjustments in dose should not be made more frequently than every 7 days. The recommended dose increment is 37.5 IU per adjustment, and should not exceed 75 IU. The maximum daily dose should not be higher than 225 IU. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should recommence treatment at a higher starting dose than in the abandoned cycle.
When an optimal response is obtained, a single injection of 5,000-10,000 IU hCG should be given 1 day after the last Menopur injection. The patient is recommended to have coitus on the day of and the day following hCG administration. Alternatively intrauterine insemination (IUI) may be performed. If an excessive response to Menopur is obtained, treatment should be stopped, hCG withheld (see Section 4.4 Special Warnings and Precautions for Use) and the patient should use a barrier method of contraception or refrain from having coitus until the next menstrual bleeding has started.

Women undergoing controlled ovarian hyperstimulation for multiple follicular development for assisted reproductive technologies (ART).

In a protocol using downregulation with a GnRH agonist, Menopur therapy should start approximately two weeks after the start of the agonist treatment. In a protocol using downregulation with a GnRH antagonist, Menopur therapy should start on day 2 or 3 of the menstrual cycle.
The recommended initial dose of Menopur is 150-225 IU daily for at least the first 5 days of treatment. Based on clinical monitoring (including ovarian ultrasound alone or in combination with measurement of oestradiol levels) subsequent dosing should be adjusted according to individual patient response, and should not exceed more than 150 IU per adjustment. The maximum daily dose given should not be higher than 450 IU daily and in most cases dosing beyond 20 days is not recommended.
When a suitable number of follicles have reached an appropriate size, a single injection of up to 10,000 IU hCG should be administered to induce final follicular maturation in preparation for oocyte retrieval. Patients should be followed closely for at least two weeks after hCG administration. If an excessive response to Menopur is obtained treatment should be stopped, hCG withheld (see Section 4.4 Special Warnings and Precautions for Use) and the patient should use a barrier method of contraception or refrain from having coitus until the next menstrual bleeding has started.

Method of administration.

Menopur is intended for subcutaneous (SC) injection after reconstitution with the solvent provided.
The powder should be reconstituted prior to use. The reconstituted solution is for multiple injections and can be used for up to 28 days. Each reconstituted Menopur 600 IU or 1200 IU vial should be for individual patient use only.

General.

Shaking should be avoided. The solution should not be used if it contains particles or if it is not clear.

Instructions for use and handling.

The powder should only be reconstituted with the solvent provided in the package.
Attach the reconstitution needle to the prefilled syringe. Inject the total contents of solvent into the vial containing the powder. Menopur 600 IU must be reconstituted with one prefilled syringe with solvent before use. Menopur 1200 IU must be reconstituted with two prefilled syringes with solvent before use. The powder should dissolve quickly to a clear solution. If not, roll the vial gently between the hands until the solution is clear. Shaking should be avoided.
The single use administration syringes with prefixed needle are graduated in FSH/LH units from 37.5-600 IU and are supplied separately. Draw up the reconstituted solution from the vial into the administration syringe for injection according to the prescribed dose. Each mL of reconstituted solution contains 600 IU FSH and LH activity.
Draw up the exact dose of reconstituted solution from the vial into the syringe for injection and administer the dose immediately.

General.

The reconstituted solution should not be administered if it contains particles or is not clear. Any unused product or waste material should be disposed in accordance with local requirements.

4.3 Contraindications

Pregnancy and lactation.
Hypersensitivity to the active substance or any of the excipients used in the formulation.
Menopur is contraindicated in women who have:
tumours of the pituitary gland or hypothalamus;
ovarian, uterine or mammary carcinoma;
gynaecological haemorrhage of unknown aetiology;
ovarian cysts or enlarged ovaries not due to polycystic ovarian disease.
In the following situations treatment outcome is unlikely to be favourable, and therefore Menopur should not be administered:
primary ovarian failure;
malformation of sexual organs incompatible with pregnancy;
fibroid tumours of the uterus incompatible with pregnancy.

4.4 Special Warnings and Precautions for Use

The active ingredient in this preparation is extracted from human urine. Therefore, the risk of transmission of a pathogen (known or unknown) cannot be completely excluded.
The luteinising hormone activity of Menopur is almost totally contributed by hCG, which has a longer plasma half-life than luteinising hormone. As a consequence, the duration of luteinising hormone activity of Menopur may differ from that of recombinant products.
Menopur is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management.
Gonadotrophin therapy requires a certain time commitment by physicians and supportive health professionals, and calls for monitoring of ovarian response with ultrasound, alone or in combination with measurement of serum oestradiol levels, on a regular basis. There is considerable interpatient variability in response to human menopausal gonadotrophin administration, with a poor response to hMG in some patients. The lowest effective dose in relation to the treatment objective should be used.
The first injection of Menopur should be performed under direct medical supervision.
Before starting treatment, the couple's infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinaemia and pituitary or hypothalamic tumours, and appropriate specific treatment given.
Patients undergoing stimulation of follicular growth, whether in the frame of a treatment for anovulatory infertility or ART procedures may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended Menopur dosage and administration regimen, and careful monitoring of therapy will minimise the incidence of such events. Acute interpretation of the indices of follicle development and maturation requires a physician who is experienced in the interpretation of the relevant tests.

Ovarian hyperstimulation syndrome (OHSS).

OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS is a syndrome that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities.
The following symptoms may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events.
Excessive ovarian response to gonadotrophin treatment seldom gives rise to OHSS unless hCG is administered to trigger ovulation. Therefore, in cases of ovarian hyperstimulation it is prudent to withhold hCG and advise the patient to refrain from coitus or to use barrier methods for at least 4 days. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event, therefore patients should be followed for at least two weeks after the hCG administration.
Adherence to recommended Menopur dosage, regimen of administration and careful monitoring of therapy will minimise the incidence of ovarian hyperstimulation and multiple pregnancy. In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.
OHSS may be more severe and more protracted if pregnancy occurs. Most often, OHSS occurs after hormonal treatment has been discontinued and reaches its maximum severity at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses.
If severe OHSS occurs, gonadotrophin treatment should be stopped if still ongoing, the patient hospitalised and specific therapy for OHSS started.
Women with polycystic ovarian syndrome (PCOS) are at higher risk of developing OHSS. Other reported risk factors that increase the risk of developing OHSS include previous episodes of OHSS, many follicles and high level of oestradiol.

Systemic diseases.

Menopur is anticipated to be used in patients who, apart from infertility, are otherwise healthy. The safety of Menopur in individuals with systemic disease, including renal or hepatic disease, has not been studied and the safety profile in these individuals is unknown. Caution should be used when prescribing Menopur to individuals with clinically relevant systemic disease.

Multiple pregnancy.

Multiple pregnancy, especially high order, carries an increased risk of adverse maternal and perinatal outcomes.
In patients undergoing ovulation induction with gonadotrophins, the incidence of multiple pregnancies is increased compared with natural conception. The majority of multiple conceptions are twins. To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.
In patients undergoing ART procedures, the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the age of the patient.
The patient should be advised of the potential risk of multiple births before starting treatment.

Pregnancy wastage.

The incidence of pregnancy wastage by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ART procedures than in the normal population.

Ectopic pregnancy.

Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy is obtained by spontaneous conception or with fertility treatment. The prevalence of ectopic pregnancy after IVF has been reported to be 2-5%, as compared to 1-1.5% in the general population.

Reproductive system neoplasms.

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. It is not yet established if treatment with gonadotrophins increases the baseline risk of these tumours in infertile women.

Congenital malformation.

The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies.

Thromboembolic events.

Women with generally recognised risk factors for thromboembolic events, such as personal or family history, severe obesity (body mass index > 30 kg/m²) or thrombophilia may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotrophins. In these women, the benefits of gonadotrophin administration need to be weighed against the risks. It should be noted however, that pregnancy itself also carries an increased risk of thromboembolic events.

Use in the elderly.

Menopur should not be used in the elderly.

Paediatric use.

Menopur should not be used in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been conducted with Menopur in humans.
Although there is no controlled clinical experience, it is expected that the concomitant use of Menopur and clomiphene citrate may enhance the follicular response. When using GnRH agonists for pituitary desensitisation, a higher dose of Menopur may be necessary to achieve adequate follicular response.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Menopur is indicated for use in infertility (see Section 4.1 Therapeutic Indications).
(Category C)
Menopur is contraindicated in women who are pregnant (see Section 4.3 Contraindications). Although no adequate animal studies have been conducted with Menopur, based on its pharmacology and reproductive studies conducted with similar products, an increase in embryonic resorptions and postimplantation loss may be expected at clinically relevant doses.
Menopur should not be used during lactation (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, Menopur is unlikely to have influence on the patient's ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The most frequently reported adverse drug reactions (ADRs) reported during treatment with Menopur in clinical trials are OHSS, headache, pelvic pain, pelvic discomfort, abdominal pain, abdominal distension, nausea and injection site reactions, with incidence rates up to 5%.
Table 1 displays the main ADRs in women treated with Menopur in clinical trials, distributed by system organ classes (SOCs) and frequency.

Post-marketing experience.

Table 2 displays ADRs reported in women treated with Menopur in the postmarketing period, distributed by system organ classes (SOCs). The ADRs seen during postmarketing experience are mentioned with unknown frequency.

Reporting suspected adverse events.

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

The effects of an overdose are unknown, nevertheless one could expect ovarian hyperstimulation syndrome to occur (see Section 4.4 Special Warnings and Precautions for Use).
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: gonadotrophins. ATC code: G03G A02.
Human chorionic gonadotrophin (hCG), a naturally occurring hormone in postmenopausal urine, is present in Menopur and is the main contributor of the LH activity.
Menopur, which contains both FSH and LH activity, induces ovarian follicular growth and development as well as gonadal steroid production in women who do not have primary ovarian failure. FSH is the primary driver of follicular recruitment and growth in early folliculogenesis, while LH is important for ovarian steroidogenesis and is involved in the physiological events leading to the development of a competent preovulatory follicle. Follicular growth can be stimulated by FSH in the total absence of LH, but the resulting follicles develop abnormally and are associated with low oestradiol levels and inability to luteinise to a normal ovulatory stimulus.
In line with the action of LH activity in enhancing steroidogenesis, oestradiol levels associated with treatment with Menopur are higher than with recombinant FSH preparations in downregulated IVF/ICSI cycles. This issue should be considered when monitoring patients' response based on oestradiol levels. The difference in oestradiol levels is not found when using low dose ovulation induction protocols in anovulatory patients.

Clinical trials.

Anovulatory infertility.

CS002 was a prospective randomised clinical trial in 184 women with WHO Group II anovulatory infertility failing to ovulate or conceive on clomiphene citrate. Ovarian stimulation was achieved using a low dose step-up protocol. The study was designed to document the noninferiority of Menopur SC versus a recombinant FSH preparation (Gonal-F) SC with respect to ovulation rate after one cycle of gonadotrophin treatment.
Menopur was demonstrated to be noninferior to rFSH with respect to ovulation rate (Table 3). In addition to the PP and ITT analyses yielding identical conclusions, the result of the sensitivity analysis adjusting for age and BMI was consistent, supporting the robustness of the conclusion drawn from the primary analysis. Significantly fewer intermediate sized follicles were observed in the Menopur group (p < 0.05). The singleton live birth rate was comparable between the two groups. The frequency of ovarian hyperstimulation syndrome and/or cancellation due to excessive response was 2.2% with Menopur and 9.8% with rFSH (p = 0.058).

Controlled ovarian hyperstimulation.

Study 0399E (European and Israeli Study Group trial, EISG), was a phase 3, randomised study in 727 infertile females undergoing ovarian stimulation to produce multiple follicles for IVF and embryo transfer (IVF/ET) after pituitary suppression with a GnRH agonist. The study was designed to demonstrate noninferiority of Menopur with respect to a recombinant FSH preparation (Gonal-F). The prespecified noninferiority limit was -10%. Randomisation was stratified by insemination technique (conventional IVF vs ICSI). Efficacy was assessed based on the primary efficacy parameter of ongoing pregnancy. The initial daily dose of gonadotrophin was 225 IU SC for 5 days. Thereafter the dose was individualised according to each patient's response, up to a maximum of 450 IU/day for a total maximum duration of stimulation of 20 days. Treatment outcomes are summarised in Table 4. The result confirmed that Menopur is noninferior to rFSH with respect to ongoing pregnancy rates. Rates of clinical and biochemical pregnancies were also comparable, as were overall safety results.

CS003 (Menopur versus recombinant FSH (Gonal-F) in vitro fertilisation trial, MERIT), was a phase 3, randomised study in 731 women undergoing IVF following downregulation with a GnRH agonist. The study was designed as a superiority study (convertible to noninferiority with a prespecified noninferiority limit of an odds ratio of 0.65) with respect to the primary outcome measure, ongoing pregnancy rate. Randomisation was stratified by age. The starting dose of gonadotrophin was 225 IU SC for the first 5 days. Thereafter the dose could be adjusted individually, according to the subject's follicular response. Treatment outcomes are summarised in Table 5. The odds ratio of ongoing pregnancy was 1.25 in favour of Menopur (95% CI 0.89-1.75). Noninferiority of Menopur with respect to rFSH was demonstrated (Table 5).

A retrospective integrated analysis, comprising 986 IVF patients and 472 ICSI patients in these two trials, has been performed. In patients undergoing IVF, the live birth rate per cycle initiated was 26.5% (130/491) with Menopur and 20.8% (103/495) with rFSH (p = 0.041). The odds ratio in favour of Menopur was 1.36 (95% CI: 1.01-1.83). Results for patients undergoing ICSI showed no statistically significant difference in live birth rate between Menopur and rFSH.

5.2 Pharmacokinetic Properties

The pharmacokinetic profile of the FSH in Menopur has been documented. After 7 days of repeated dosing with 150 IU Menopur in downregulated healthy female volunteers, maximum plasma FSH concentration (baseline corrected) (mean ± SD) was 8.9 ± 3.5 IU/L for the SC administration. Maximum FSH concentrations were reached within 7 hours. After repeated administration, FSH was eliminated with a half-life (mean ± SD) of 30 ± 11 hours for the SC administration. Although the individual LH concentration versus time curves show an increase in the LH concentration after dosing with Menopur, the data available were too sparse to be subjected to a pharmacokinetic analysis. In a bioequivalence study (CS05) utilising a single dose of 450 IU of Menopur in downregulated healthy female volunteers, serum hCG was below the assay limit of detection at baseline in all subjects, consistent with their nonpregnant premenopausal state, and rose following administration of Menopur in a time profile similar to that of FSH.
Human menopausal gonadotrophin is excreted primarily via the kidneys.
The pharmacokinetics of Menopur in patients with renal or hepatic impairment has not been investigated.

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of Menopur has not been investigated. Gonadotrophins are naturally occurring proteins and unlikely to pose a genotoxic risk.

Carcinogenicity.

No carcinogenicity studies have been performed in animals.

6 Pharmaceutical Particulars

6.1 List of Excipients

Powder.

Lactose monohydrate, polysorbate 20, dibasic sodium phosphate heptahydrate, phosphoric acid.

Solvent.

Metacresol, water for injections.

6.2 Incompatibilities

Menopur should not be administered in the same injection with other products.

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 in a refrigerator (2-8°C). Do not freeze. Store in the original container. To reduce microbiological hazard, the reconstituted solution should be stored in a refrigerator and must be discarded after 28 days. Chemical and in use stability have been demonstrated for reconstituted product stored for up to 28 days at not more than 25°C.