MENOPUR MULTIDOSE 1200 IU

Patient leaflet in accordance with the Pharmacists’

Regulations (Preparations) - 1986

This medicine is dispensed with a doctor’s prescription only

Menopur Multidose 600 IU and 1200 IU

Powder and solvent for reconstituting a solution for subcutaneous

or intramuscular injection

Composition:

Menopur Multidose 600 IU

Each vial with powder contains menotropin (hMG):

LH 600 IU and FSH 600 IU

Menopur Multidose 1200 IU

Each vial with powder contains menotropin (hMG):

LH 1200 IU and FSH 1200 IU

Inactive ingredients: See section 6 ‘Additional information’. See also

‘Important information about some of this medicine’s ingredients’ in section 2.

Read the entire leaflet carefully before you start using this medicine. This

leaflet contains concise information about the medicine. If you have any further

questions, consult your doctor or pharmacist.

This medicine has been prescribed to treat your illness. Do not pass it on to

others. It may harm them, even if it seems to you that their illness is similar to

yours.

1. What is this medicine intended for?

In women: Infertility that is caused by ovary failure, promoting follicle growth in

fertility treatments.

In men: Infertility that is caused by testicular failure, promoting semen production

in combination with hCG treatment.

Therapeutic group: Gonadotropins.

2. Before using Menopur

Do not use this medicine if:

In women:

you are pregnant or breastfeeding

you have vaginal bleeding for an unknown reason

you have tumors of the womb (uterus), ovaries or breasts

you have cysts in your ovaries or are diagnosed with enlarged ovaries that

are not due to polycystic ovarian disease (a condition that prevents eggs from

being released from the ovaries)

you are having early menopause

you have certain physical problems in your reproductive organs (womb,

fallopian tubes, ovaries or cervix)

your womb has been removed (hysterectomy)

you have fibroids (tumors in your womb that are not cancer)

In men:

you have cancer of your prostate gland and/or of the testicles

Special warnings about using this medicine:

Before starting treatment, you and your partner should be evaluated by a doctor

for the causes of your fertility problems. Special attention should be given to

diagnosis and treatment of the following conditions:

underactive thyroid or adrenal glands

high levels of a hormone called prolactin (hyperprolactinemia)

tumors of the pituitary gland (a gland located on the base of the brain which

produces certain hormones, including growth hormone)

tumors of the hypothalamus (an area located under the part of the brain called

the thalamus which controls the conditions within your body including body

temperature and blood pressure)

During the course of treatment with this medicine:

Consult your doctor immediately if you experience:

pain or swelling of the abdomen

nausea or vomiting

weight gain

difficulty in breathing

decreased urination

Tell your doctor straight away, even if the symptoms described above

develop some days after you are given the last injection. These can be

signs of excessive activity in the ovaries and it might get worse.

If these symptoms become severe, the fertility treatment must be stopped and

you should receive treatment in hospital.

Keeping to your prescribed dose and careful monitoring of your treatment will

reduce your chances of getting these symptoms.

If you stop using MENOPUR you might still experience these symptoms. Please

contact your doctor immediately if any of these symptoms occur.

While you are being treated with this medicine, your doctor will normally arrange

for you to have ultrasound scans and sometimes blood tests to monitor your

response to treatment.

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

ectopic pregnancy (pregnancy outside of the womb),if you have a history of

fallopian tube disease

miscarriage

multiple pregnancy )twins, triplets, etc.(

congenital malformations (physical defects present in baby at birth)

Women who were given fertility treatment with multiple medicines have developed

tumors in the ovaries and other reproductive organs. It is not known if treatment

with hormones like MENOPUR causes these problems.

Blood clot formation inside blood vessels (veins or arteries) are more likely to

occur in women who are pregnant. Fertility treatment can increase the chances

of this happening, especially if you are overweight or are known to have a blood

clotting disease (thrombophilia) or if you or someone in your family (blood

relative( has had blood clots. Tell your doctor if you think this applies to you.

Children: This medicine is not used in children.

Other medicines and MENOPUR

If

you

are

taking

or

have

recently

taken

other

medicines,

including

nonprescription medications and dietary supplements, tell your doctor or

pharmacist.

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.

Pregnancy and breastfeeding

Do not use MENOPUR during pregnancy or breastfeeding.

Driving and using machines

MENOPUR is unlikely to affect your ability to drive and use machines.

Important information about some of this medicine’s ingredients

MENOPUR contains less than 1 mmol sodium (23 mg) per dose, so it is essentially

‘sodium-free’.

The medicine also contains lactose )which is a type of sugar(. If you have been

told by your doctor that you cannot tolerate or digest certain sugars, talk to your

doctor before starting treatment with this medicine.

. How to use MENOPUR?

Always use this medicine according to your doctor’s instructions. Check with your

doctor or pharmacist if you are not sure about your dose or about how to take this

medicine.

This medicine is not intended for children or the elderly.

Do not swallow this medicine!

Do not exceed the recommended dose.

The recommended dose depends on the reason you are being treated. Your

doctor will monitor how you respond to treatment. This will help your doctor to

work out what dose you need and how long you need to use MENOPUR.

How to inject yourself:

You must be trained by the clinic staff to make the injection before you use this

product.

Your first self-injection will be performed under medical supervision.

Your doctor will monitor your reaction to treatment. If an excessive

response occurs, your doctor may decide to stop treatment with MENOPUR

and not give you the hCG injection. In this case, you will have to use a

barrier method of contraception (such as a condom) or not have sexual

intercourse until your next period has started. For the following treatment

cycle your doctor will give you a lower dose of MENOPUR than before.

Directions for use:

For injection under the skin or into a muscle

Dissolving MENOPUR

MENOPUR 1200 IU is provided as a powder in a vial and must be dissolved with

both syringes with liquid )solvent( before it is injected. The solvent which you

will use to dissolve the powder is provided in two pre filled syringes supplied in

the package.

MENOPUR 600 IU is provided as a powder in a vial and must be dissolved with

one syringe with liquid )solvent( before it is injected. The solvent which you

will use to dissolve the powder is provided in a pre filled syringe supplied in the

package.

Please note: One drop of solvent can dissolve all the powder immediately,

leading to the impression that no powder was present in the vial. Check the vial

for powder before adding the solvent.

As this vial contains medication for several days of treatment, you need to make

sure you only draw up the dose that was prescribed by your doctor. Note that

the dose of Menopur you are prescribed is measured in IU. To obtain the correct

dose you must use one of the graduated syringes in the package that are marked

with IU units of LH and FSH.

What to do:

Remove the cap from the vial of powder and the syringe cap from the

syringe with solvent )Figure 1(.

Firmly attach the thick needle (reconstitution needle) to the syringe with

solvent and remove the needle cap )Figure 2(.

Insert the needle through the center of the rubber stopper of the powder

vial and slowly inject all of the solvent. Aim at the vial wall to avoid

creating bubbles )Figure 3(.

If you are preparing MENOPUR 1200 IU, mix the powder in the vial

with the contents of both syringes of solvent before using. After

you have injected the content of the first syringe with solvent into

the powder vial, gently twist the syringe off the needle, leaving

the needle inserted in the vial. Remove the cap from the second

syringe with solvent and firmly attach the syringe to the needle

in the vial. Slowly inject the solvent; aim at the vial wall to avoid

creating bubbles.

After adding the solvent from each syringe with solvent to the powder vial a slight

over-pressure is created in the vial. Therefore, each time, after you have added

the solvent from a syringe, let go of the syringe plunger and allow it rise up by

itself for about 10 seconds. This will release the pressure in the vial )Figure 4(.

Remove the syringe and the needle used to reconstitute the medicine.

The powder should quickly dissolve )within 2 minutes( to form a clear solution.

To help the powder dissolve, swirl the solution. Do not shake as this will cause

air bubbles to form )Figure 5(. Do not use the solution if it is not clear or if it

contains particles.

Take a disposable syringe with pre attached needle and insert the needle

vertically into center of the vial. Turn the vial upside down and draw the

prescribed

dose

)Figure

REMEMBER: This vial contains medication for several days of treatment.

You need to make sure you only draw up the dose that was prescribed by

your doctor.

Injecting MENOPUR

Remove the syringe from the vial and pull the plunger out to draw a small amount

of air into the syringe )Figure 7(.

Gently flick the administration syringe and then push the plunger in carefully until

the first drops of solution come out )Figure 8(.

Choose an injection site according to instructions from your doctor or nurse (for

example the front of the thigh, abdomen, etc.(. Disinfect the injection site.

10. To inject, pinch the skin produce a fold and insert the needle in one swift motion

at 90 degrees to the body. Push the plunger in to inject the solution and then pull

the needle out of the skin )Figure 9(.

11. After removing the needle, apply pressure to the injection site to stop any

bleeding. Gently massaging the injection site will help to disperse the solution

under the skin.

12. For the next injection, repeat steps 6 to 11.

13. Use a new disposable syringe with pre-attached needle each time.

If you have taken an overdose, or if a child has accidentally swallowed

some medicine, immediately see a doctor or go to a hospital emergency room

and bring the medicine package with you.

If you forget to take the medicine at the scheduled time, do not take a double

dose. Adhere to the treatment as recommended by your doctor.

Do not take medicines in the dark! Check the label and dose every time you

take medicine. Wear glasses if you need them.

If you have any further questions about using this medicine, consult your

doctor or pharmacist.

4. Side effects

Like with all medicines, using MENOPUR may cause side effects in some users.

Do not be alarmed by this list of side effects; you may not experience any of

them.

In women:

If you notice any of the following signs, consult your doctor immediately. They

may be signs of ovarian hyperstimulation syndrome )OHSS(, especially in

women with polycystic ovaries, and you may need urgent medical treatment.

Symptoms include:

nausea

vomiting

diarrhea

weight gain

pain or swelling of the abdomen

In cases of severe OHSS:

fluid build-up in the abdomen, pelvis, and/or chest

difficulty in breathing

decreased urination (producing small amounts of urine when you go to the

toilet or going to the toilet less often)

formation of blood clots (thromboembolism)

twisted ovary (ovarian torsion)

If you notice any of the above signs, consult your doctor immediately!

Side effects that can happen in both women and men: Stop using MENOPUR

if you experience an allergic reaction that includes the following side

effects: itching, skin rashes, itching, swelling of the face, lips or throat and

difficulty in breathing. In these cases, consult your doctor or go to hospital

immediately.

Common side effects (affect 1 10 in 100 users):

headache

nausea

abdominal pain and swelling

pelvic pain

overstimulation of the ovaries resulting in high levels of activity (OHSS)

pain or inflammation at the injection site (redness, bruising, swelling and/or

itching)

Uncommon side effects (affect up to 1 in 1,000 users):

vomiting

discomfort in the stomach

diarrhea

fatigue

dizziness

sacs of fluid in the ovaries (ovarian cysts)

breast pain, breast discomfort, breast tenderness, nipple pain and breast

swelling

hot flashes

Rare side effects (affect 1 10 in 10,000 users):

acne

rash

Side effects of unknown frequency:

allergic reactions

eyesight disturbances

pain in muscles and joints (for example back pain, neck pain and pain in arms

and legs)

twisted ovary (ovarian torsion) as a complication of OHSS

itching

hives

If you experience any side effect, if any side effect gets worse, or if you experience

a side effect not mentioned in this leaflet, consult your doctor.

Reporting side effects

You can report side effects to the Ministry of Health by following the link

‘Reporting Side Effects of Drug Treatment’ on the Ministry of Health home page

(www.health.gov.il( which links to an online form for reporting side effects. You

can also use this link: https://sideeffects.health.gov.il

5. How to store the medicine?

Prevent poisoning! To prevent poisoning, keep this, and all other medicines, in a

closed place, out of the reach and sight of children and/or infants. Do not induce

vomiting unless explicitly instructed to do so by a doctor.

Do not use the medicine after the expiry date )exp. date( which is stated on the

package. The expiry date refers to the last day of that month.

Storage conditions

Store in a refrigerator at 2°C-8°C. Do not freeze. Store in the original package to

protect from light.

After dissolving, store below 25°C for 28 days but no longer than the expiry

date.

Do not freeze, either before or after dissolving.

6. Additional information

In addition to the active ingredients, this medicine also contains:

Powder:

lactose

monohydrate,

polysorbate

sodium

phosphate

dibasic

heptahydrate,

phosphoric

acid.

Solvent:

metacresol, water for injection.

What the medicine looks like and contents of the pack:

MENOPUR Multidose 600 IU: Each pack of medicine contains a vial of

powder, a pre filled syringe with solvent for reconstitution, a needle for

reconstitution, 9 disposable syringes with pre-attached needle.

MENOPUR Multidose 1200 IU: Each pack of medicine contains a vial of

powder, 2 pre filled syringes with solvent for reconstitution, a needle for

reconstitution, 18 disposable syringes with pre-attached needle.

Not all pack sizes may be marketed.

Registration holder’s name and address: Ferring Pharmaceuticals

Ltd., 8 Hashita Street, Industrial Park, Caesarea, 3088900.

Manufacturer’s name and address: Ferring, Germany.

Revised in May 2020.

Registration number of the medicine in the Ministry of Health’s National Drug

Registry:

MENOPUR multidose 600 IU: 147 66 33326

MENOPUR multidose 1200 IU: 147 67 33343

DOR MEN 600IU&1200IU 0720 11

1.

NAME OF THE MEDICINAL PRODUCT

MENOPUR multidose 600 IU

MENOPUR multidose 1200 IU

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

MENOPUR 600 IU: Each vial of powder contains highly purified menotrophin (human

menopausal gonadotrophin, HMG) corresponding to 600 IU human follicle stimulating

hormone (FSH) and 600 IU human luteinizing hormone (LH) activity.

MENOPUR 1200 IU: Each vial of powder contains highly purified menotrophin (human

menopausal gonadotrophin, HMG) corresponding to 1200 IU follicle stimulating hormone

(FSH) and 1200 IU human luteinizing hormone (LH) activity.

Human Chorionic Gonadotrophin (hCG), a naturally occurring hormone

in postmenopausal urine, is present in MENOPUR and contributes to the overall luteinizing

hormone activity. Menotrophin is produced from human urine.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Appearance of powder: white to off-white lyophilised cake.

Appearance of solvent: clear colourless solution.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

For the treatment of Sterility in females with hypo or normogonadotropic ovarian

insufficiency: stimulation of follicle growth.

Sterility in males with hypo or normogonadotropic hypogonadism: In combination with HCG

to spermatogenesis.

4.2

Posology and method of administration

Treatment with MENOPUR should be initiated under the supervision of a physician

experienced in the treatment of fertility problems.

Method of administration

MENOPUR is intended for subcutaneous (S.C.) or intramuscular (I.M.) 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. Vigorous

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

not clear.

Dosage

Dosage regimens described below are identical for S.C. and I.M. administration.

There are great inter-individual 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 anovulation (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 IU to 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 and hCG withheld (see section 4.4) 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 line with clinical trials with MENOPUR that involved downregulation with GnRH

agonists, MENOPUR therapy should start approximately 2 weeks after the start of agonist

treatment. 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.

In protocols not involving downregulation with GnRH agonist, MENOPUR therapy should

start on day 2 or 3 of the menstrual cycle. It is recommended to use the dose ranges and

regimen of administration suggested above for protocols with downregulation with GnRH

agonists.

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 2 weeks after hCG

administration. If an excessive response to MENOPUR is obtained treatment should be

stopped and hCG withheld (see section 4.4) and the patient should use a barrier method of

contraception or refrain from having coitus until the next menstrual bleeding has started.

Renal/hepatic impairment

Patients with renal and hepatic impairment have not been included in clinical trials (see

section 5.2).

4.3

Contraindications

MENOPUR is contraindicated in women and men with:

- Tumours of the pituitary gland or hypothalamus

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Women

- Ovarian, uterine or mammary carcinoma

Pregnancy and lactation

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 administrated:

Primary ovarian failure

Malformation of sexual organs incompatible with pregnancy

Fibroid tumours of the uterus incompatible with pregnancy

Structural abnormalities in which a satisfactory outcome cannot be expected, for example,

tubal occlusion (unless superovulation is to be induced for IVF), ovarian dysgenesis,

absent uterus or premature menopause.

Tumours in the testes

Prostate carcinoma

4.4

Special warnings and precautions for use

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

preferably in combination with measurement of serum oestradiol levels, on a regular basis.

There is considerable inter-patient variability in response to menotrophin administration, with

a poor response to menotrophin 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, hyperprolactinemia 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 regimen of

administration, 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.

If urinary oestrogen levels exceed 540 nmol (150 micrograms)/24 hours, or if plasma 17 beta-

oestradiol levels exceed 3000 pmol/L (800 picograms/ml), or if there is any steep rise in

values, there is an increased risk of hyperstimulation and MENOPUR treatment should be

immediately discontinued and human chorionic gonadotrophin withheld. Ultrasound will

reveal any excessive follicular development and unintentional hyperstimulation.

The severe form OHSS may be life-threatening and is characterised by large ovarian cysts

(prone to rupture), acute abdominal pain, ascites, very often hydrothorax and occasionally

thromboembolic phenomena. Other symptoms that may be observed include: 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, haemoperitoneum, pleural

effusions and acute pulmonary distress.

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 (see sections 4.2 and 4.8). Patients undergoing controlled ovarian hyperstimulation

may be at an increased risk of developing hyperstimulation in view of the excessive oestrogen

response and multiple follicular development. 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.

This syndrome occurs with higher incidence in patients with polycystic ovarian 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 to 5%, as compared to 1 to 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

tumors 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/m

) 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.

4.5

Interaction with other medicinal products and other forms of interaction

No drug/drug 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

agonist for pituitary desensitisation, a higher dose of MENOPUR may be necessary to

achieve adequate follicular response.

4.6

Fertility, pregnancy and lactation

Fertility

MENOPUR is indicated for use in infertility (see section 4.1).

Pregnancy

MENOPUR is contraindicated in women who are pregnant (see section 4.3).

There are no or limited amount of data from the use of menotrophins in pregnant women. No

animal studies have been carried out to evaluate the effects of MENOPUR during pregnancy

(see section 5.3).

Breast-feeding

MENOPUR is contraindicated in women who are breast-feeding (see section 4.3).

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

Undesirable effects

The most frequently reported adverse drug reactions (ADR) during treatment with

MENOPUR in clinical trials are ovarian hyperstimulation syndrome (OHSS), abdominal pain,

headache,

abdominal distension and

injection site reactions and injection site pain.

None of

these ADRs have been reported with an incidence rate of more than 5%.

The table below displays the main ADRs in women treated with MENOPUR in clinical trials

distributed by system organ classes (SOCs) and frequency.

ADRs seen during post-marketing

experience are mentioned with unknown frequency.

System Organ

Class

Common

(> 1/100 and <

1/10)

Uncommon

(> 1/1000 and <

1/100)

Rare

(>

1/10000

and <

1/1000)

Unknown

Eye disorders

Visual disorders

Gastrointestinal

disorders

Abdominal pain,

Abdominal

distension,

nausea,

Vomiting,

Abdominal

discomfort,

Diarrhoea

General disorders

and administration

site condition

Injection site

reactions

Fatigue

Immune system

disorders

Hypersensitivity

reactions

Musculoskeletal &

connective tissue

disorders

Musculoskeletal

pain

Nervous system

disorders

Headache

Dizziness

Reproductive

system disorders

OHSS

pelvic pain

Ovarian cyst, Breast

complaints

Ovarian torsion

Skin and

Acne,

Pruritus,

subcutaneous

tissue disorders

Rash

Urticaria

Vascular disorders

hot flush

Most frequently reported injection site reaction was injection site pain.

Cases of localised or generalised allergic reactions

,

including anaphylactic

reaction, along

with associated symptomatology have been reported rarely.

Musculoskeletal pain includes arthralgia, back pain, neck pain and pain in extremities.

Gastrointestinal

symptoms

associated

with

OHSS

such

abdominal

distension

discomfort, nausea, vomiting and diarrhoea have been reported with MENOPUR in

clinical trials. In cases of severe OHSS ascites and pelvic fluid collection, pleural

effusion, dyspnoea, oliguria, thromboembolic events and ovarian torsion have been

reported as rare complications.

Pelvic pain includes ovarian pain and adnexa uteri pain.

Breast complaints include breast pain, breast tenderness, breast discomfort, nipple pain and

breast swelling.

Reporting suspected adverse reactions after authorization of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product. Any suspected adverse events should be reported to the Ministry of Health

according to the National Regulation by using an online form

https://sideeffects.health.gov.il/

4.9

Overdose

The effects of an overdose is unknown, nevertheless one could expect ovarian

hyperstimulation syndrome to occur (see section 4.4).

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Gonadotrophins

ATC code: G03G A02

Menotrophin (Human Menopausal Gonadotrophin, HMG) is a gonadotrophin extracted from

the urine of post menopausal women. It has both luteinising hormone and follicle stimulating

hormone activity in a 1:1 ratio. Human Chorionic Gonadotrophin (hCG), a naturally

occurring hormone in postmenopausal urine, is present in MENOPUR and is the main

contributor of the LH activity.

Menotrophin (HMG) directly affects the ovaries and the testes. HMG has a gametropic and

steroidogenic effect.

In the ovaries, the FSH-component in HMG induces an increase in the number of growing

follicles and stimulates their development. FSH increases the production of oestradiol in the

granulosa cells by aromatising androgens that originate in the Theca cells under the influence

of the LH-component.

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

luteinize to a normal ovulatory stimulus.

In line with the action of LH activity in enhancing stereoidogenesis, 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 patient´s response based on oestradiol levels. In the testes, FSH induces the

transformation of premature to mature Sertoli cells. It mainly causes the maturation of the

seminal canals and the development of the spermatozoa. However, a high concentration of

androgens within the testes is necessary and can be attained by a prior treatment using hCG.

5.2

Pharmacokinetic properties

The pharmacokinetics of Menotrophin following intramuscular or subcutaneous

administration shows great interindividual variability. After 7 days of repeated dosing with

150 IU MENOPUR in downregulated healthy female volunteers, maximum plasma FSH

concentrations (baseline-corrected) (mean

SD) were 8.9

3.5 IU/L and 8.5

3.2 IU/L for

the SC and IM administration, respectively. The area under the curve (AUC

) of FSH

concentration was (mean ± SD) 180 ± 77 h.IU/L and 166 ± 67 h.IU/L for SC and IM

administration, respectively.Maximum FSH concentrations were reached within 7 hours for

both routes of administration. After repeated administration, FSH was eliminated with a half-

life (mean

SD) of 30

11 hours and 27

9 hours for the SC and IM administration,

respectively. 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.

Menotrophin 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

Non-clinical data reveal no special hazard for humans, which is not known from the extensive

clinical experience. Reproduction toxicity studies have not been carried out to evaluate the

effects of MENOPUR during pregnancy or post partum as MENOPUR is not indicated during

these periods.

MENOPUR consist of naturally occurring hormones and should be expected to be non-

genotoxic. Carcinogenicity studies have not been carried out as the indication is for short term

treatment.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Powder:

Lactose monohydrate, polysorbate 20, sodium phosphate dibasic heptahydrate (for pH

adjustment), phosphoric acid (concentrated) (for pH adjustment).

Solvent:

Metacresol, water for injection.

6.2

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other

medicinal products.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials After reconstitution,

the solution may be stored for a maximum of 28 days at not more than-25°C. Do not freeze.

6.4

Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to

protect from light.

For storage condition of the reconstituted medicinal product, see section 6.3

6.5

Nature and contents of container

MENOPUR 600 IU:

Powder: 2 ml colourless glass (type I glass) vial with rubber stopper closed with a cap.

Solvent: 1 ml pre-filled syringe (type I glass) with rubber (type I) tip cap and plunger rubber

stopper .

Each pack contains 1 vial of powder, 1 pre-filled syringe with solvent for reconstitution, 1

needle for reconstitution and 9 disposable syringes for administration graduated in FSH/LH

units with pre-fixed needles.

MENOPUR 1200 IU:

Powder: 2 ml colourless glass (type I glass) vial with rubber stopper closed with a cap.

Solvent: 1 ml pre-filled syringe (type I glass) with rubber (type I) tip cap and plunger rubber

stopper.

Each pack contains 1 vial of powder, 2 pre-filled syringes with solvent for reconstitution, 1

needle for reconstitution, 18 disposable syringes for administration graduated in FSH/LH

units with pre-fixed needles.

6.6

Special precautions for disposal

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 pre-filled syringe with solvent before use.

MENOPUR 1200 IU must be reconstituted with two pre-filled 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. Vigorous shaking should be avoided.

The reconstituted solution should not be administered if it contains particles or is not clear.

The single use administration syringes are graduated in FSH/LH units from 37.5 – 600 IU.

Draw up the exact prescribed dose of reconstituted solution from the vial

using one of the

disposable syringes provided for injection and administer the dose immediately.. Each ml of

reconstituted solution contains 600 IU FSH and LH.

Discard the syringe after use.

Each reconstituted MENOPUR 600 IU or 1200 IU vial should be for individual patient use

only.

Any unused product or waste material should be disposed in accordance with local

requirements.

7.

MANUFACTURER

Ferring GmbH Germany

8.

LICENSE HOLDER

Ferring Pharmaceuticals Ltd.

Hashita St., Industrial Park Caesarea 3088900

9. MARKETING AUTHORISATION NUMBER(S)

Menopur Multidose 600 IU: 147 66 33326

Menopur Multidose 1200 IU: 147 67 33343

Revised in May 2020.