PUREGON SOLUTION FOR INJECTION

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS REGULATIONS

(PREPARATIONS) 1986

This medicine can be sold under doctor's prescription only

PUREGON

®

SOLUTION FOR INJECTION

150 IU, 300 IU, 600 IU, 900 IU

Solution for Injection

Each cartridge contains:

Follitropin beta 150 IU/ 0.18 ml

Follitropin beta 300 IU/ 0.36 ml

Follitropin beta 600 IU/ 0.72 ml

Follitropin beta 900 IU/ 1.08 ml

For a list of inactive ingredients see section 6.1 "What PUREGON contains".

Read all of this leaflet carefully before you start using this medicine.

This leaflet contains concise information about PUREGON. If you have any further questions, ask your

doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their

medical condition seems similar to yours.

PUREGON is not intended for use in children.

PUREGON is not intended for pregnant women.

1. WHAT IS THE MEDICINE INTENDED FOR?

PUREGON is used to treat infertility in any of the following situations:

Women

In women who do not ovulate and do not respond to treatment with clomifene citrate, PUREGON can be

used to cause ovulation.

In women undergoing assisted reproduction techniques, including in vitro fertilisation (IVF) and other

methods, PUREGON can bring about the development of multiple follicles.

In men who are infertile due to lowered hormone levels, PUREGON can be used for the production of

sperm.

Therapeutic group: Gonadotrophins (sex hormones).

PUREGON solution for injection contains follitropin beta, a hormone known as follicle-stimulating hormone

(FSH).

FSH belongs to the group of gonadotrophins (sex hormones), which play an important role in human fertility

and reproduction. In women, FSH is needed for the growth and development of follicles in the ovaries.

Follicles are small round sacs that contain the egg cells.

In men, FSH is needed for the production of sperm.

2. BEFORE YOU TAKE PUREGON

2.1 Do not use PUREGON if you:

are hypersensitive (allergic) to follitropin beta or any of the other ingredients of PUREGON (listed in

section 6.1)

have a tumour of the ovary, breast, uterus, testis or brain (pituitary gland or hypothalamus)

have heavy or irregular vaginal bleeding where the cause is unknown.

have ovaries that do not work because of a condition called primary ovarian failure

have ovarian cysts or enlarged ovaries not caused by polycystic ovarian syndrome (PCOS)

have malformations of the sexual organs which make a normal pregnancy impossible

have fibroid tumours in the uterus which make a normal pregnancy impossible

are a man and are infertile because of a condition called primary testicular failure.

2.2 Special warnings concerning use of PUREGON

Before starting treatment with PUREGON, tell your doctor if you:

have had an allergic reaction to certain antibiotics (neomycin and/or streptomycin)

have uncontrolled pituitary gland or hypothalamic problems

have an underactive thyroid gland (hypothyroidism)

have adrenal glands that are not working properly (adrenocortical insufficiency)

have high prolactin levels in the blood (hyperprolactinemia)

have any other medical conditions (for example, diabetes, heart disease, or any other long-term

disease).

If you are a woman:

Ovarian hyperstimulation syndrome (OHSS)

Your doctor will check the effects of the treatment regularly to be able to choose the correct dose of

PUREGON from day to day. You may regularly have ultrasound scans of the ovaries. Your doctor may also

check blood hormone levels. This is very important since too high a dose of FSH may lead to rare but

serious complications in which the ovaries are overly stimulated and the growing follicles become larger

than normal. This serious medical condition is called ovarian hyperstimulation syndrome (OHSS). In rare

cases, severe OHSS may be life-threatening. OHSS causes fluid to build up suddenly in your stomach and

chest areas and can cause blood clots to form. Call your doctor right away if you notice severe abdominal

swelling, pain in the stomach area (abdomen), feeling sick (nausea), vomiting, sudden weight gain due to

fluid buildup, diarrhoea, decreased urine output or trouble breathing (see also section 4, “SIDE EFFECTS”).

→ Regular monitoring of the response to FSH-treatment helps to prevent ovarian overstimulation.

Contact your doctor immediately if you are experiencing stomach pains, also if this occurs some days after

the last injection has been given.

Multiple Pregnancy or birth defects

After treatment with gonadotrophin preparations, there is an increased chance of having multiple

pregnancies, even when only one embryo is transferred into the uterus. Multiple pregnancies carry an

increased health risk for both the mother and her babies around the time of birth. Furthermore, multiple

pregnancies and characteristics of the patients undergoing fertility treatment (e.g. age of the female, sperm

characteristics, genetic background of both parents) may be associated with an increased risk of birth

defects.

Pregnancy complications

There is a slightly increased risk of a pregnancy outside the uterus (an ectopic pregnancy). Therefore, your

doctor should perform an early ultrasound examination to exclude the possibility of pregnancy outside the

uterus.

In women undergoing fertility treatment there may be a slightly higher chance of a miscarriage.

Blood clot (Thrombosis)

Treatment with PUREGON, just as pregnancy itself, may increase the risk of having a blood clot

(thrombosis). Thrombosis is the formation of a blood clot in a blood vessel.

Blood clots can lead to serious medical conditions, such as:

blockage in your lungs (pulmonary embolus)

stroke

heart attack

blood vessel problems (thrombophlebitis)

a lack of blood flow (deep venous thrombosis) that may result in a loss of your arm or leg.

Please discuss this with your doctor, before starting treatment, especially:

if you already know you have an increased chance of having thrombosis

if you, or anyone in your immediate family, have ever had a thrombosis

if you are severely overweight.

Ovarian torsion

Ovarian torsion has been reported and may occur after treatment with gonadotropins including PUREGON.

Ovarian torsion is the twisting of an ovary. Twisting of the ovary could cause the blood flow to the ovary to

be cut off.

Before starting to use this medicine, tell your doctor if you:

have ever had ovarian hyperstimulation syndrome OHSS

are pregnant or think that you may be pregnant

have ever had stomach (abdominal) surgery

have ever had a twisting of an ovary

have past or current cysts in your ovary or ovaries.

Ovarian and Other Reproductive System Tumours

There have been reports of ovarian and other reproductive system tumors in women who have had

infertility treatment. It is not known if treatment with fertility medicines increases the risk of these tumors in

infertile women.

Other medical conditions

In addition, before starting to use this medicine, tell your doctor if you:

have been told by a doctor that pregnancy would be dangerous for you.

If you are a man:

Men with too much FSH in their blood

Increased FSH blood levels are a sign of damage to the testicles. PUREGON is usually not effective in

such cases. To check the effects of treatment, your doctor may ask you for a semen sample to be

analysed, four to six months after the start of treatment.

2.3 Taking other medicines

If you are taking or have recently taken other medicines, including non-prescription medicines and

nutritional supplements, you should tell the attending doctor or pharmacist.

If PUREGON is used in a combination with clomifene citrate, the effect of PUREGON may be increased. If

a GnRH agonist (a medicine used to prevent early ovulation) has been given, higher doses of PUREGON

may be needed.

2.4 Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine. You should not use PUREGON if you

are already pregnant, or think you might be pregnant.

PUREGON may affect milk production. It is unlikely that PUREGON is passed into breast milk. If you are

breast-feeding, tell your doctor before using PUREGON.

2.5 Driving and using machines

PUREGON is unlikely to affect your ability to drive or use machines.

2.6 Important information about some of the ingredients of PUREGON

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, i.e. essentially “sodium-

free”.

2.7 Children

PUREGON is not intended for use in children.

3. HOW TO TAKE PUREGON?

Always take PUREGON as instructed by the doctor. You should check with your doctor or pharmacist if you

are not sure.

The dosage and duration of treatment will be determined by the doctor only.

The usually recommended dose is:

Dosage in women

Your doctor will decide on your starting dose. This dose may be adjusted during your treatment period.

Further details on the treatment schedule are given below.

There are large differences between women in the response of the ovaries to FSH, which makes it

impossible to set a dosage schedule which is suitable for all patients. To find the right dosage, your doctor

will check your follicle growth by means of ultrasound scanning, and measurement of the amount of

oestradiol (female sex hormone) in the blood.

* Women who are not ovulating

A starting dose is set by your doctor. This dose is continued for at least seven days. If there is no

ovarian response, the daily dose will then be gradually increased until follicle growth and/or plasma

oestradiol levels indicate a proper response. The daily dose is then maintained until a follicle of proper

size is present. Usually, 7 to 14 days of treatment are sufficient. PUREGON treatment is then stopped

and ovulation will be induced by giving human chorionic gonadotrophin (hCG).

* Medically assisted reproduction programs, for instance IVF

A starting dose is set by your doctor. This dose is continued for at least the first four days. After this,

your dose may be adjusted, based upon your ovarian response. When a sufficient number of follicles of

proper size are present, the final phase of maturation of the follicles is induced by giving hCG. Retrieval

of the egg(s) is performed 34-35 hours later.

Dosage in men

PUREGON is usually prescribed at a dose of 450 IU per week, mostly in 3 dosages of 150 IU, in

combination with another hormone (hCG), for at least 3 to 4 months. The treatment period equals the

development time of sperm and the time in which improvement can be expected. If your sperm production

has not started after this period, your treatment may carry on for at least 18 months.

Do not exceed the recommended dose.

How are the injections given

The very first injection of PUREGON should only be given in the presence of a doctor or nurse.

PUREGON solution for injection in cartridges has been developed for use in the Puregon Pen. The

separate instructions for using the pen must be followed carefully. Do not use the cartridge if the solution

contains particles or if the solution is not clear.

Using the pen, injections just under the skin (in the lower stomach, for example) can be given by yourself or

your partner. Your doctor will tell you when and how to do this. If you inject yourself with PUREGON, follow

the instructions carefully to give PUREGON properly and with minimal discomfort.

Instructions for injection

Take the pen out of its case, remove the cap from the pen, unscrew the body from the cartridge

holder.

Insert the PUREGON cartridge into the cartridge holder with the cap of the cartridge going in first.

Screw the pen on again. Make sure that no gap is left and that the blue arrow marked at the end of

the cartridge holder points to the yellow mark at the end of the pen body.

Use a new needle for each injection. Before attaching the needle, disinfect the end of the PUREGON

cartridge (placed inside the pen) and the open end of the cartridge holder with some alcohol.

Remove the paper seal from the outer needle shield and push the pen steadily into the needle shield.

Screw the needle in firmly. Remove the outer and inner needle shield.

Hold the pen with the needle pointing upwards, gently tap the cartridge holder with your finger to allow

the air bubbles to rise to the top of the needle. A droplet of liquid will form at the tip of the needle.

If you do not see liquid at the tip of the needle, dial the dosage knob one click and press the injection

button. Make sure that a droplet of liquid has formed at the tip of the needle. Repeat this step until a

droplet is observed at the tip of the needle.

The pen is now ready for injecting PUREGON.

Dial the orange dosage knob until the dot located between the two marks in the middle of the dosage

scale is aligned with the desired dose prescribed by your doctor.

If you accidentally dialed past the correct dose, turn the dosage knob past the 450 IU mark, as far as

it will turn. The dosage scale should move freely.

Press the injection button in and begin to readjust the dosage, from zero upwards. No medicine is lost

in this process.

If you try to correct your error by dialing in the opposite direction you will get the exact dose, but will

lose some of the medicine.

Disinfect the injection site with alcohol, and let the alcohol dry somewhat before continuing.

It is advisable to administer the injection in the abdomen, below the navel.

Pinch the skin where you will administer the injection between your thumb and forefinger and with

your other hand insert the entire needle into the skin at a 90 degree angle.

Press the injection button and inject until the dosage scale shows “0”.

Wait 5 seconds before removing the needle from the skin. Pull the needle out gently and place a

sterile pad on the injection site.

Insert the needle into the outer needle shield. Remove the needle from the pen and store the pen in a

safe place.

If you use more PUREGON than you should

Tell your doctor immediately.

Too high a dose of PUREGON may cause hyperstimulation of the ovaries (OHSS). This may be noticed as

pain in the stomach. If you are troubled by stomach pains, tell your doctor immediately (see also section 4,

“SIDE EFFECTS”).

If you have taken an overdose, or if a child has accidentally swallowed the medicine, proceed immediately

to a hospital emergency room and bring the package of the medicine with you.

If you forget to use PUREGON

If you forget a dose do not use a double dose to make up for a missed dose.

→ Contact your doctor.

How can you contribute to the success of the treatment?

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

you take your medicine. Wear

glasses if you need them.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. SIDE EFFECTS

Like all medicines, PUREGON can cause side effects, in some of the users.

Do not be alarmed by reading the list of side effects, you may not suffer from any of them.

Serious side effects in women

A complication with FSH treatment is hyperstimulation of the ovaries. Ovarian overstimulation may develop

into a medical condition called ovarian hyperstimulation syndrome (OHSS), which can be a serious

medical problem. The risk can be reduced by careful monitoring of follicular development during treatment.

Your doctor will do ultrasound scans of your ovaries to carefully monitor the number of maturing follicles.

Your doctor may also check blood hormone levels. Pain in the stomach, feeling sick or diarrhoea are the

first symptoms. In more severe cases symptoms may include enlargement of the ovaries, accumulation of

fluid in the abdomen and/or chest (which may cause sudden weight gain due to fluid buildup) and the

occurrence of blood clots in the circulation (see section 2.2, “Special warnings concerning use of

PUREGON”).

→ Contact your doctor immediately if you are experiencing stomach pains, or any of the other symptoms of

ovarian hyperstimulation, also if this occurs some days after the last injection.

If you are a woman:

Common side effects (may affect up to 1 in 10 people):

Headache

Injection site reactions (such as bruising, pain, redness, swelling and itching)

Ovarian hyperstimulation syndrome (OHSS)

Pelvic pain

Stomach pain and/or bloating

Uncommon side effects (may affect up to 1 in 100 people):

Breast complaints (including tenderness)

Diarrhoea, constipation or stomach discomfort

Enlargement of the uterus

Feeling sick (nausea)

Hypersensitivity reactions (such as rash, redness, hives and itching)

Ovarian cysts or enlargement of the ovaries

Ovarian torsion (twisting of the ovaries)

Vaginal bleeding

Rare side effects (may affect up to 1 in 1,000 people):

Blood clots (this may also occur in the absence of unwanted overstimulation of the ovaries, see section

2.2, “Special warnings concerning use of PUREGON”).

Pregnancy outside the uterus (an ectopic pregnancy), miscarriage and multiple pregnancies have also been

reported. These side effects are not considered to be related to the use of PUREGON, but to Assisted

Reproductive Technology (ART) or subsequent pregnancy.

If you are a man:

Common side effects (may affect up to 1 in 10 people):

Acne

Injection site reactions (such as hardening and pain)

Headache

Rash

Some breast development

Testicular cyst

If a side effect appears, if any of the side effects gets serious or if you notice a side effect not mentioned in

this leaflet, consult your doctor.

Side effects can be reported to the Ministry of Health by using the online form for adverse events reporting

which is on the Ministry of Health Homepage: www.health.gov.il

or by following the link:

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic%40moh.health

.gov.il

5. HOW TO STORE PUREGON?

Avoid Poisoning! This medicine, as all other medicines, must be stored in a safe place out of the

reach and sight of children and/or infants, in order to avoid poisoning. Do not induce vomiting unless

explicitly instructed to do so by a doctor!

Do not use PUREGON after the expiry date (exp. date) which is stated on the pack. The expiry date

refers to the last day of the indicated month.

Storage conditions:

Store in a refrigerator (2°C – 8°C). Do not freeze.

May be stored by the patient at or below 25ºC for a single period of not more than three months.

Keep the medicine in the outer carton.

Make a note of when you start storing the product out of the refrigerator.

Once the rubber inlay of a cartridge is pierced by a needle, the product may be stored for a maximum of

28 days.

Please put the day of first use of the cartridge on the dosing record table as shown in the Instruction

Manual of the Puregon Pen.

Discard used needles immediately after injection.

Do not mix any other drug into the cartridges. Empty cartridges must not be refilled.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how

to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

6.1 What PUREGON contains?

The active substance is: follitropin beta.

PUREGON cartridge contains either: 150 IU, 300 IU, 600 IU, 900 IU of follitropin beta.

In addition to the active ingredient the medicine also contains inactive ingredients: sucrose, sodium

citrate, L-methionine, polysorbate 20 and benzyl alcohol in water for injections. The pH may have been

adjusted with sodium hydroxide and/or hydrochloric acid.

6.2 What PUREGON looks like and contents of the pack

PUREGON solution for injection is a clear, colourless aqueous solution.

Pack size:

PUREGON 300 IU is available in packs of 1 multi-dose cartridge of 0.480 ml, and 2 packs with 3 pen

needles each.

PUREGON 600 IU is available in packs of 1 multi-dose cartridge of 0.840 ml, and 2 packs with 3 pen

needles each.

PUREGON 900 IU is available in packs of 1 multi-dose cartridge of 1.230 ml, and 3 packs with 3 pen

needles each.

Marketing authorization holder:

Merck Sharp & Dohme (Israel-1996) Company Ltd., P.O.Box 7121, Petah-Tikva 49170.

Manufacturer:

Merck Sharp & Dohme Corp., New-Jersey, USA.

This Leaflet was checked and approved by the Ministry of Health on October 2015

Drug registration no. listed in the official registry of the Ministry of Health:

PUREGON solution for injection: 130.52.30898

1.

NAME OF THE MEDICINAL PRODUCT

Puregon solution for injection

150 IU/0.18 mL, 300 IU/0.36 mL, 600 IU/0.72 mL or 900 IU/1.08 mL.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

One cartridge contains a net total dose of 150 IU, 300 IU, 600 IU or 900 IU recombinant follicle-stimulating

hormone (FSH) in 0.18, 0.36, 0.72 or 1.08 ml aqueous solution. The solution for injection contains the active

substance follitropin beta, produced by genetic engineering of a Chinese hamster ovary (CHO) cell line, in a

concentration of 833 IU/mL aqueous solution. This strength corresponds to 83.3 microgram of protein / ml

(specific in vivo bioactivity equal to approximately 10,000 IU FSH / mg protein). Excipient(s) with known

effect:

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, i.e. essentially

‘sodium-free’.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection.

Clear and colourless solution.

In cartridges, designed to be used in conjunction with a pen injector.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

In the female

Puregon is indicated for the treatment of female infertility in the following clinical situations

Anovulation (including polycystic ovarian syndrome, PCOS) in women who have been unresponsive

to treatment with clomifene citrate.

Controlled ovarian hyperstimulation to induce the development of multiple follicles in medically

assisted reproduction programs [e.g. in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-

fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)].

In the male

Deficient spermatogenesis due to hypogonadotrophic hypogonadism.

4.2

Posology and method of administration

Treatment with Puregon should be initiated under the supervision of a physician experienced in the

treatment of fertility problems.

The first injection of Puregon should be performed under direct medical supervision.

Posology

Dosage in the female

There are great inter- and intra-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. This requires ultrasound assessment of follicular

development. The concurrent determination of serum oestradiol levels may also be useful.

When using the pen injector, it should be realised that the pen is a precision device which accurately delivers

the dose to which it is set. It was shown that on average an 18% higher amount of FSH is given with the pen

compared with a conventional syringe. This may be of particular relevance when switching between the pen-

injector and a conventional syringe within one treatment cycle. Especially when switching from a syringe to

the pen, small dose adjustments may be needed to prevent too high a dose being given.

Based on the results of comparative clinical studies, it is considered appropriate to give a lower total dosage

of Puregon over a shorter treatment period

than generally used for urinary FSH, not only in order to optimise

follicular development but also to reduce the risk of unwanted ovarian hyperstimulation (see section 5.1).

Clinical experience with Puregon is based on up to three treatment cycles in both indications. Overall

experience with IVF indicates that in general the treatment success rate remains stable during the first four

attempts and gradually declines thereafter.

Anovulation

A sequential treatment scheme is recommended starting with daily administration of 50 IU Puregon. The

starting dose is maintained for at least seven days. If there is no ovarian response, the daily dose is

then gradually increased until follicle growth and/or plasma oestradiol levels indicate an adequate

pharmacodynamic response. A daily increase of oestradiol levels of 40-100% is considered to be

optimal. The daily dose is then maintained until pre-ovulatory conditions are reached. Pre-ovulatory

conditions are reached when there is ultrasonographic evidence of a dominant follicle of at least 18 mm

in diameter and/or when plasma oestradiol levels of 300-900 picograms/mL (1,000-3,000 pmolL) are

attained. Usually, 7 to 14 days of treatment is sufficient to reach this state. The administration of

Puregon is then discontinued and ovulation can be induced by administering human chorionic

gonadotrophin (hCG).

If the number of responding follicles is too high or oestradiol levels increase too rapidly, i.e. more than a

daily doubling for oestradiol for two or three consecutive days, the daily dose should be decreased.

Since follicles of over 14 mm may lead to pregnancies, multiple pre-ovulatory follicles exceeding 14 mm

carry the risk of multiple gestations. In that case hCG should be withheld and pregnancy should be

avoided to prevent multiple gestations.

Controlled ovarian hyperstimulation in medically assisted reproduction programs

Various stimulation protocols are applied. A starting dose of 100-225 IU is recommended for at least the

first four days. Thereafter, the dose may be adjusted individually, based upon ovarian response. In

clinical studies, it was shown that maintenance dosages ranging from 75-375 IU for six to twelve days

are sufficient, although longer treatment may be necessary.

Puregon can be given either alone, or, to prevent premature luteinisation, in combination with a GnRH

agonist or antagonist. When using a GnRH agonist, a higher total treatment dose of Puregon may be

required to achieve an adequate follicular response.

Ovarian response is monitored by ultrasound assessment. The concurrent determination of serum

oestradiol levels may also be useful. When ultrasound assessment indicates the presence of at least

three follicles of 16-20 mm, and there is evidence of a good oestradiol response (plasma levels of about

300-400 picograms/mL (1,000-1,300 pmol/L) for each follicle with a diameter greater than 18 mm), the

final phase of maturation of the follicles is induced by administration of hCG. Oocyte retrieval is

performed 34-35 hours later.

Dosage in the male

Puregon should be given at a dosage of 450 IU/week, preferably divided in 3 dosages of 150 IU,

concomitantly with hCG. Treatment with Puregon and hCG should be continued for at least 3 to 4 months

before any improvement in spermatogenesis can be expected. To assess the response, semen analysis is

recommended 4 to 6 months after the beginning of treatment. If a patient has not responded after this period,

the combination therapy may be continued; current clinical experience indicates that treatment for up to 18

months or longer may be necessary to achieve spermatogenesis.

Paediatric population

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

Method of administration

Puregon solution for injection in cartridges has been developed for use in the Puregon Pen and should be

administered subcutaneously. The injection site should be alternated to prevent lipoatrophy.

Using the pen, injection of Puregon can be carried out by the patient or partner, provided that proper

instructions are given by the physician.

Self administration of Puregon should only be performed by

patients

who are well-motivated, adequately trained and with access to expert advice.

4.3

Contraindications

For males and females

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

Tumours of the ovary, breast, uterus, testis, pituitary or hypothalamus.

Primary gonadal failure.

Additionally for females

Undiagnosed vaginal bleeding.

Ovarian cysts or enlarged ovaries, not related to polycystic ovarian syndrome (PCOS).

Malformations of the reproductive organs incompatible with pregnancy.

Fibroid tumours of the uterus incompatible with pregnancy.

4.4

Special warnings and precautions for use

Antibiotic hypersensitivity reactions

Puregon may contain traces of streptomycin and/or neomycin. These antibiotics may cause

hypersensitivity reactions in susceptible persons.

Infertility evaluation before starting treatment

Before starting treatment, the couple's infertility should be assessed as appropriate. In particular,

patients should be evaluated for hypothyroidism, adrenocortical insufficiency, hyperprolactinemia and

pituitary or hypothalamic tumours, and appropriate specific treatment given.

In females

Ovarian Hyperstimulation Syndrome (OHSS)

OHSS is a medical event distinct from uncomplicated ovarian enlargement. Clinical signs and symptoms of

mild and moderate OHSS are abdominal pain, nausea, diarrhoea, mild to moderate enlargement of ovaries

and ovarian cysts. Severe OHSS may be life-threatening. Clinical signs and symptoms of severe OHSS are

large ovarian cysts, acute abdominal pain, ascites, pleural effusion, hydrothorax, dyspnoea, oliguria,

haematological abnormalities and weight gain. In rare instances, venous or arterial thromboembolism may

occur in association with OHSS. Transient liver function test abnormalities suggestive of hepatic dysfunction

with our without morphologic changes on liver biopsy have also been reported in association with OHSS.

OHSS may be caused by administration of human Chorionic Gonadotropin (hCG) and by pregnancy

(endogenous hCG). Early OHSS usually occurs within 10 days after hCG administration and may be

associated with an excessive ovarian response to gonadotropin stimulation. Late OHSS occurs more than 10

days after hCG administration, as a consequence of the hormonal changes with pregnancy. Because of the

risk of developing OHSS, patients should be monitored for at least two weeks after hCG administration.

Women with known risk factors for a high ovarian response may be especially prone to the development of

OHSS during or following treatment with Puregon. For women having their first cycle of ovarian stimulation,

for whom risk factors are only partially known, close observation for ealy signs and symptoms of OHSS is

recommended.

Follow current clinical practice for reducing the risk of OHSS during Assisted Reproductive

Technology (ART). Adherence to the recommended Puregon dose and treatment regimen and careful

monitoring of ovarian response is important to reduce the risk of OHSS. To monitor the risk of OHSS,

ultrasonographic assessment of follicular development should be performed prior to treatment and at regular

intervals during treatment; the concurrent determination of serum oestradiol levels may also be useful. In

ART there is an increased risk of OHSS with 18 or more follicles of 11 mm or more in diameter.

If OHSS develops, standard and appropriate management of OHSS should be implemented and followed.

Multiple Pregnancy

Multiple pregnancies and births have been reported for all gonadotropin treatments, including Puregon.

Multiple gestations, especially high order, carries an increased risk of adverse maternal (pregnancy and

delivery complications) and perinatal (low birth weight) outcomes. For anovulatory women undergoing

ovulation induction, monitoring follicular development with transvaginal ultrasonography may aid in

determining whether or not to continue the cycle in order to reduce the risk of multiple pregnancies. The

concurrent determination of serum oestradiol levels may also be useful. The patients should be advised of

the potential risks of multiple births before starting treatment.

In women undergoing Assisted Reproduction Technologies (ART) procedures, the risk of a multiple

pregnancy is mainly related to the number of embryos transferred. When used for an ovulation induction

cycle, appropriate FSH dose adjustment(s) should prevent multiple follicle development.

Ectopic Pregnancy

Infertile women undergoing ART have an increased incidence of ectopic pregnancies. Early ultrasound

confirmation that a pregnancy is intrauterine is therefore important.

Spontaneous Abortion

Rates of pregnancy loss in women undergoing assisted reproduction techniques are higher than in the

normal population.

Vascular Complications

Thromboembolic events, both in association with and separate from OHSS, have been reported following

treatment with gonadotropins, including Puregon. Intravascular thrombosis, which may originate in venous or

arterial vessels, can result in reduced blood flow to vital organs or the extremities. In women with generally

recognised risk factors for thromboembolic events, such as a personal or family history, severe obesity or

thrombophilia, treatment with gonadotropins, including Puregon, may further increase this risk. In these

women the benefits of gonadotropin administration, including Puregon, need to be weighed against the risks.

It should be noted, however, that pregnancy itself also carries an increased risk of thrombosis.

Congenital Malformations

The incidence 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 gestations.

Ovarian Torsion

Ovarian torsion has been reported after treatment with gonadotropins, including Puregon. Ovarian torsion

may be associated with other risk factors such as OHSS, pregnancy, previous abdominal surgery, past

history of ovarian torsion, previous or current ovarian cyst and polycystic ovaries.

Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate

detorsion.

Ovarian and other Reproductive System Neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in

women who have undergone multiple treatment regimens for infertility treatment. It is not established

whether or not treatment with gonadotropins increases the risk of these tumors in infertile women.

Other Medical Conditions

Medical conditions that contraindicate pregnancy should also be evaluated before starting treatment with

Puregon.

In males

Primary Testicular Failure

Elevated endogenous FSH levels in men are indicative of primary testicular failure. Such patients are

unresponsive to Puregon/hCG therapy.

4.5

Interaction with other medicinal products and other forms of interaction

Concomitant use of Puregon and clomifene citrate may enhance the follicular response. After pituitary

desensitisation induced by a GnRH agonist, a higher dose of Puregon may be necessary to achieve an

adequate follicular response.

4.6

Fertility, Pregnancy and lactation

Fertility

Puregon is used in the treatment of women undergoing ovarian induction or controlled ovarian

hyperstimulation in assisted reproduction programmes. In males Puregon is used in the treatment of deficient

spermatogenesis due to hypogonadotrophic hypogonadism. For posology and method of administration, see

section 4.2.

Pregnancy

The use of Puregon during pregnancy is not indicated.

In case of inadvertent exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic

effect of recombinant FSH.

However, to date, no particular malformative effect has been reported. No teratogenic effect has been

observed in animal studies.

Breast-feeding

There is no information available from clinical or animal studies on the excretion of follitropin beta in milk. It is

unlikely that follitropin beta is excreted in human milk due to its high molecular weight. If follitropin beta would

be excreted in human milk, it would be degraded in the gastrointestinal tract of the child. Follitropin beta may

affect milk production.

4.7

Effects on ability to drive and use machines

Puregon has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

Clinical use of Puregon by the intramuscular or subcutaneous routes may lead to local reactions at the site of

injection (3% of all patients treated). The majority of these local reactions are mild and transient in nature.

Generalised hypersensitivity reactions have been observed uncommonly (approximately 0.2% of all patients

treated with follitropin beta).

Treatment of females:

In approximately 4% of the women treated with follitropin beta in clinical trials, signs and symptoms related to

ovarian hyperstimulation syndrome (OHSS) have been reported (see section 4.4). Adverse reactions related

to this syndrome include pelvic pain and/or congestion, abdominal pain and/or distension, breast complaints

and ovarian enlargement.

The table below lists the adverse reactions with follitropin beta reported in clinical trials in females according

to system organ class and frequency; common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100).

SOC

Frequency

Adverse reaction

Nervous system disorders

Common

Headache

Gastrointestinal disorders

Common

Abdominal distension

Abdominal pain

Uncommon

Abdominal discomfort

Constipation

Diarrhoea

Nausea

Reproductive system and

breast disorders

Common

OHSS

Pelvic pain

Uncommon

Breast Complaints

Metrorrhagia

Ovarian cyst

Ovarian enlargement

Ovarian torsion

Uterine enlargement

Vaginal haemorrhage

General disorders and

Common

Injection site reaction

administration site conditions

Uncommon

Generalised hypersensitivity

reaction

1. Breast complaints include tenderness, pain and/or engorgement and nipple pain

2. Local reactions at the site of injection include: bruising, pain, redness, swelling and itching

3. Generalised hypersensitivity reaction include erythema, urticaria, rash and pruritus

In addition, ectopic pregnancy, miscarriage and multiple gestations have been reported. These are

considered to be related to ART or subsequent pregnancy.

In rare instances, thromboembolism has been associated with follitropin beta / hCG therapy as with other

gonadotrophins.

Treatment of males:

The table below lists the adverse reactions with follitropin beta reported in a clinical trial in males (30 patients

dosed), according to system organ class and frequency; common (≥ 1/100 to < 1/10).

SOC

Frequency

1

Adverse reaction

Nervous system disorders

Common

Headache

Skin and subcutaneous

tissue disorders

Common

Acne

Rash

Reproductive system and

breast disorders

Common

Epididymal cyst

Gynaecomastia

General disorders and

administration site

conditions

Common

Injection site reaction

Adverse reactions that are reported only once are listed as common because a single report

raises the frequency above 1%.

Local reactions at the site of injection include induration and pain.

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

or by email

(adr@MOH.HEALTH.GOV.IL).

4.9

Overdose

No data on acute toxicity of Puregon in humans is available, but the acute toxicity of Puregon and of urinary

gonadotrophin preparations in animal studies has been shown to be very low. Too high a dosage of FSH

may lead to hyperstimulation of the ovaries (see section 4.4).

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: sex hormones and modulators of the genital system, gonadotrophins; ATC

code: G03G A06.

Puregon contains a recombinant FSH. This is produced by recombinant DNA technology, using a Chinese

hamster ovary cell line transfected with the human FSH subunit genes. The primary amino acid sequence is

identical to that of natural human FSH. Small differences in the carbohydrate chain structure are known to

exist.

Mechanism of Action

FSH is indispensable in normal follicular growth and maturation, and gonadal steroid production. In the

female the level of FSH is critical for the onset and duration of follicular development, and consequently for

the timing and number of follicles reaching maturity. Puregon can thus be used to stimulate follicular

development and steroid production in selected cases of disturbed gonadal function. Furthermore, Puregon

can be used to promote multiple follicular development in medically assisted reproduction programs [e.g. in

vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm

injection (ICSI)]. Treatment with Puregon is generally followed by administration of hCG to induce the final

phase of follicle maturation, resumption of meiosis and rupture of the follicle.

Clinical Efficacy and Safety

In clinical studies comparing recFSH (follitropin beta) and urinary FSH for controlled ovarian stimulation in

women participating in an assisted reproduction technology (ART) program and for ovulation induction (see

tables 1 and 2 below), Puregon was more potent than urinary FSH in terms of a lower total dose and a

shorter treatment period needed to trigger follicular maturation.

For controlled ovarian stimulation, Puregon resulted in a higher number of oocytes retrieved at a lower total

dose and with a shorter treatment period, when compared to urinary FSH.

Table 1: Results of study 37608 (randomized, group comparative clinical study comparing safety and efficacy

of Puregon with urinary FSH in controlled ovarian stimulation).

Puregon

(n = 546)

u-FSH

(n = 361)

Mean no. of oocytes retrieved

10.84*

8.95

Mean total dose (no, of 75 IU ampoules)

28.5*

31.8

Mean duration of FSH stimulation (days)

10.7*

11.3

* Differences between the 2 groups were statistically significant (p<0.05).

For ovulation induction, Puregon resulted in a lower median total dose and shorter median duration of

treatment when compared to urinary FSH.

Table 2: Results of study 37609 (randomized, group comparative clinical study comparing safety and efficacy

of Puregon with urinary FSH in ovulation induction).

Puregon

(n = 105)

u-FSH

(n = 66)

Mean no. of follicles ≥ 12 mm

≥ 15 mm

≥ 18 mm

3.6*

Median total dose (IU)

750*

1035

Median duration of treatment (days)

10.0*

13.0

* Differences between the 2 groups were statistically significant (p<0.05).

Restricted to women with ovulation induced (Puregon, n = 76; u-FSH, n = 42).

5.2

Pharmacokinetic properties

Absorption

After subcutaneous administration of Puregon, maximum concentration of FSH is reached within about 12

hours. Due to the sustained release from the injection site and the elimination half-life of about 40 hours

(ranging from 12 to 70 hours), FSH levels remain increased for 24-48 hours. Due to the relatively long

elimination half-life, repeated administration of the same dose will lead to plasma concentrations of FSH that

are approximately 1.5-2.5 times higher than after single dose administration. This increase enables

therapeutic FSH concentrations to be reached.

The absolute bioavailability of subcutaneously administered Puregon is approximately 77%.

Distribution, biotransformation and elimination

Recombinant FSH is biochemically very similar to urinary human FSH and is distributed, metabolised, and

excreted in the same way.

5.3

Preclinical safety data

Single-dose administration of Puregon to rats induced no toxicologically significant effects. In repeated-dose

studies in rats (two weeks) and dogs (13 weeks) up to 100-fold the maximal human dose, Puregon induced

no toxicologically significant effects. Puregon showed no mutagenic potential in the Ames test and in the in

vitro chromosome aberration test with human lymphocytes.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Puregon solution for injection contains:

Sucrose

Sodium citrate

Benzyl alcohol

L-methionine

Polysorbate 20

Water for injections

The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid.

6.2

Incompatibilities

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

products.

6.3

Shelf life

3 years.

Once the rubber inlay of a cartridge is pierced by a needle, the product may be stored for a maximum of 28

days.

6.4

Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze.

May be stored by the patient at or below 25ºC for a single period of not more than three months.

Keep the medicine in the outer carton.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5

Nature and contents of container

Boxes of Puregon solution for injection contain 1 cartridge of Puregon and 6 (300 IU and 600 IU cartridges)

or 9 (900 IU cartridges) needles to be used with the Puregon Pen.

The cartridges are of borosillicate tube (class 1) glass, with a rubber piston and an aluminium crimp-cap with

a rubber inlay.

Cartridges contain 833 IU of FSH activity per mL aqueous solution. Cartridges with a net dose of 300 IU

contain a minimum of 400 IU in 0.480 mL; those of 600 IU contain a minimum of 700 IU in 0.840 mL; those of

900 IU contain a minimum of 1025 IU in 1.230 mL.

6.6

Special precautions for handling and disposal

Do not use if the solution contains particles or if the solution is not clear.

Puregon solution for injection in cartridges is designed for use in conjunction with the Puregon Pen. The

instructions for using the pen must be followed carefully.

Air bubbles must be removed from the cartridge before injection (see instructions for using the pen).

Empty cartridges must not be refilled.

Puregon cartridges are not designed to allow any other drug to be mixed in the cartridges.

Discard used needles immediately after injection.

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

requirements.

7.

MANUFACTURER

Merck Sharp & Dohme Corp., New-Jersey, USA

8.

MARKETING AUTHORIZATION HOLDER

Merck Sharp & Dohme (Israel – 1996) Company Ltd

P.O.Box 7121, Petah-Tikva 49170

9.

REGISTRATION NUMBER(S)

130.52.30898

Revised in April 2020