Consumer medicine information

Menopur

Menopausal gonadotrophin, human

BRAND INFORMATION

Brand name

Menopur

Active ingredient

Menopausal gonadotrophin, human

Schedule

What is in this leaflet

This leaflet answers some common questions about Menopur.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Menopur against the benefits he/she expects it will have for you.

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

Keep this leaflet. You may need to read it again.

What Menopur is used for

Menopur contains highly purified human menopausal gonadotrophin (hMG), also known as menotrophin, as the active ingredient. It is obtained from the urine of post-menopausal women.

hMG is a mixture of three hormones with follicle stimulating hormone (FSH) activity and luteinising hormone (LH) activity found naturally in humans.

Menopur belongs to a class of medicines called gonadotrophins.

Menopur is used to treat infertility (reproduction related conditions) in women.

Menopur is used in women who are not ovulating (not producing eggs). It helps women become pregnant by stimulating the ovarian follicles to release an egg.

Menopur is also used to stimulate the ovarian follicles in women undergoing Assisted Reproductive Technology (ART) such as IVF/ET (in vitro fertilisation/embryo transfer), GIFT (gamete intra-fallopian transfer) and ICSI (intracytoplasmic sperm injection) to help them become pregnant.

Your doctor will be able to talk to you about your specific fertility problem.

Menopur is given only by or under the supervision of your doctor.

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

This medicine is not addictive.

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

This medicine is not expected to affect your ability to drive a car or operate machinery.

Before you use Menopur

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.

When you must not use it

Do not use Menopur if you have or have had an allergy to:

any medicine containing menotrophin or human menopausal gonadotrophin
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not use Menopur if:

you have tumours of the uterus (womb), ovaries, breasts, pituitary gland or hypothalamus
you have cysts on your ovaries or enlarged ovaries (unless caused by polycystic ovarian disease)
you have any physical defects of the uterus (womb) or other sexual organs
you suffer from bleeding from the vagina where the cause is not known
you have fibroids of the uterus (womb)
you are pregnant
you are breastfeeding.

Do not use Menopur after the expiry date printed on the pack.

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

If you are not sure whether you should have this medicine, talk to your doctor.

Before you use it

Tell your doctor if you have allergies to:

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

Tell your doctor if you have or have had any medical conditions, especially the following:

problems with genital organs
adrenal problems
thyroid problems
diabetes, or a family history of diabetes
primary ovarian failure
polycystic ovarian syndrome (PCOS)
ovarian hyperstimulation syndrome (OHSS)
any problems with your liver, kidneys or other organs
you are obese (BMI > 30 kg/m2) or have a condition that increases your risk of having blood clots (thrombophilia), or if you or someone in your family (blood relative) has had blood clots. Blood clot formation inside the blood vessels (veins or arteries) is more likely to occur in women who are pregnant. Infertility treatment can increase the chances of this happening, especially in women with these pre-existing conditions.

If you have not told your doctor about any of the above, tell him/her before you are given Menopur.

Taking other medicines

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

If Menopur is used at the same time as clomiphene citrate the effect on the ovaries may be increased.

How Menopur is used

How it is used

Menopur is given as an injection under the skin (subcutaneous), usually near the stomach.

If your doctor or nurse decides you can give the injections yourself, they will teach you the injection technique.

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

Follow all instructions given to you by your doctor carefully.

Please see the leaflet supplied with Menopur for detailed instructions on how it is to be reconstituted and administered.

How much is used

The dose of Menopur will depend on your condition and will be determined by your doctor.

Women who are not ovulating (not producing eggs):
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.

The starting dose is normally 75-150 IU daily. This dose may be increased according to your response to the treatment up to maximum of 225 IU per day. A particular dose should be given for at least 7 days before the dose is changed. The cycle of treatment should be abandoned if there is no response after 4 weeks.

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. The initial dose of Menopur is normally 150-225 IU. This dose may be increased 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.

If enough egg sacs are present, you will be given a single injection of a medicine called human chorionic gonadotrophin (hCG) to induce ovulation (release of an egg).

Your doctor will closely monitor your progress for at least 2 weeks after you have received the hCG injection.

How often is it given

The length of treatment varies with each patient being treated. Your doctor will be able to answer this question.

It is possible to have more than one treatment cycle of Menopur.

Overdose

As your doctor will tell you the dose of Menopur, it is very unlikely that you will receive too much.

In women, hyperstimulation of the ovaries, known as ovarian hyperstimulation syndrome (OHSS) is a rare but potentially serious complication of infertility therapy and can be the result of excessive doses of Menopur. Without proper hospital management this condition may even be fatal.

The initial symptoms may consist of abdominal pain, abdominal swelling and/or nausea and vomiting.

While you are using Menopur

Take special care with Menopur if:

you feel pain in the abdomen or in the pelvic region
you get swelling in the abdomen
you experience nausea
you experience vomiting
you develop diarrhoea
you gain weight
you feel tired
you experience difficulty breathing
you notice decreased urination.

Tell your doctor straight away, 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. Therefore, symptoms might become severe.

If these symptoms become severe, the infertility treatment should be stopped and you should receive treatment in hospital.

Keeping to your recommended dose will reduce your chances of getting these symptoms.

Things you must do

Tell your doctor immediately if you become pregnant while using Menopur.

Tell your doctor if you have abnormal vaginal bleeding while using Menopur.

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 other doctors, dentists, and pharmacists who are treating you that you are using Menopur.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are using Menopur.

If you are going to have surgery, tell the surgeon or anaesthetist that you are using Menopur.

Things to be careful of

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

Pregnancy risks

Being treated with hormones like Menopur can increase the risk of:

ectopic pregnancy (pregnancy outside of the womb). Women who have a history of fallopian tube disease are also at increased risk of ectopic pregnancy whether they conceive naturally or following IVF
miscarriage
multiple pregnancy (twins, triplets, etc)
congenital malformations (physical defects present in baby at birth).

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.

Side effects

Tell your doctor or nurse or pharmacist as soon as possible if you do not feel well after you have Menopur.

This medicine helps most people with infertility, 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 attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

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

local reaction around the injection site such as redness, itchiness, tenderness, pain or discomfort, warmth, burning or stinging or swelling
breast swelling, breast pain, tenderness or discomfort (including nipple pain)
generalised rash or itchiness
acne
headache
fever
hot flush
dizziness
tiredness
generally feeling unwell
problems with your eyes
pain in muscles or joints, including back, neck and/or extremities.

These may be mild or rare side effects and are usually short-lived.

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

swelling in your hands, feet or ankles.

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

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you experience any of the following.

sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
abdominal or pelvic pain, abdominal swelling, nausea, vomiting and/or diarrhoea (initial symptoms of ovarian hyperstimulation syndrome)
Menopur sometimes stimulates the ovaries too much. This is called ovarian hyperstimulation syndrome (OHSS) and can be a serious medical problem. OHSS may cause pelvic pain, diarrhoea and weight gain, or breathing problems. It may also make you urinate less. In cases of severe OHSS accumulation of fluid in abdomen, pelvis and/or chest cavity and twisting of ovaries (ovarian torsion) have been reported as rare complications. In rare cases, patients with this problem have had serious lung problems. This includes fluid in the lungs, trouble breathing, and worsening of asthma
blood clots and strokes.

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

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using Menopur

Storage

Keep Menopur where children cannot reach it.

Keep Menopur in the original pack until it is time for it to be used.

Store Menopur 600 IU and 1200 IU in a refrigerator (2 to 8°C). Do not freeze. After reconstitution, the solution may be stored for up to 28 days.

Disposal

If you are self-injecting, you should discard all sharps into a disposal unit.

If you have any Menopur that has expired or is left over from your treatment refer this to your clinic.

Product description

What it looks like

Menopur 600 IU
The product is supplied as a pack containing one vial of powder, one pre-filled syringe with solvent for reconstitution and one needle for reconstitution. Disposable alcohol pads and single-use administration syringes (graduated in FSH/LH units with pre-fixed needles) are supplied separately.

Menopur 1200 IU
The product is supplied as a pack containing one vial of powder, two pre-filled syringes with solvent for reconstitution and one needle for reconstitution. Disposable alcohol pads and single-use administration syringes (graduated in FSH/LH units with pre-fixed needles) are supplied separately.

Ingredients

Menopur 600 IU
Each vial of Menopur contains human menopausal gonadotrophin corresponding to follicle stimulating hormone activity (FSH) 600 IU and luteinizing hormone activity (LH) 600 IU as the active ingredient.

Menopur 1200 IU
Each vial of Menopur contains human menopausal gonadotrophin corresponding to follicle stimulating hormone activity FSH 1200 IU and luteinizing hormone activity LH 1200 IU as the active ingredient.

The other ingredients in the powder are:

lactose monohydrate
polysorbate 20
sodium phosphate
phosphoric acid.

The other ingredients in the solvent are:

meta-cresol and
water for injections.

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

Sponsor:

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 November 2020.

Australian Register Number:
Menopur 600 IU: AUST R 161984
Menopur 1200 IU: AUST R 161985

DOCS#12118 v19

Published by MIMS February 2021

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.

Excipients 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. Therefore, the dosage should 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.

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 effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

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.