GONAL-f 300 IU/0.5 ml (22 micrograms/0.5 ml) solution forinjection in pre-filled pen

What GONAL-f is

GONAL-f contains a medicine called ?follitropin alfa?. Follitropin alfa is a type of ?Follicle Stimulating Hormone? (FSH) which belongs to the family of hormones called ?gonadotropins?. Gonadotropins are involved in reproduction and fertility.

What GONAL-f is used for

In adult women, GONAL-f is used:

• to help release an egg from the ovary (ovulation) in women that cannot ovulate and that did not respond to treatment with a medicine called ?clomiphene citrate?.
• together with another medicine called ?lutropin alfa? (?Luteinising Hormone? or LH) to help release egg from the ovary (ovulation) in women that are not ovulating because their body is producing very little gonadotropins (FSH and LH).
• to help develop several follicles (each containing an egg) in women undergoing assisted reproductive technology procedures (procedures that may help you to become pregnant) such as ? in vitro fertilisation?, ?gamete intra-fallopian transfer? or ?zygote intra-fallopian transfer?.

In adult men, GONAL-f is used:

• together with another medicine called ?human Chorionic Gonadotropin? (hCG) to help produce sperm in men that are infertile due to a low level of certain hormones.

You and your partner?s fertility should be evaluated before the treatment is started by a doctor experienced in treating fertility disorders.

Do not use GONAL-f

• if you are allergic (hypersensitive ) to Follicle Stimulating Hormone or any of the other ingredients of GONAL-f listed in section 6.
• if you have a tumour in your hypothalamus or pituitary gland (both are parts of the brain).
• If you are a woman:
• with large ovaries or sacs of fluids within the ovaries (ovarian cysts) of unknown origin.
• with unexplained vaginal bleeding.
• with cancer in your ovaries, womb or breasts.
• with a condition that usually makes normal pregnancy impossible, such as ovarian failure (early menopause), or malformed reproductive organs.
• If you are a man:
• with damaged testicles that cannot be healed.

Do not use GONAL-f if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before using this medicine.

Take special care with GONAL-f

Porphyria
Tell your doctor before you start treatment, if you or any member of your family have porphyria (an inability to break down porphyrins that may be passed on from parents to children). Tell your doctor straight away if:

• your skin becomes fragile and easily blistered, especially skin that has been frequently in the sun, and/or
• you have stomach, arm or leg pain. In case of the above events your doctor may recommend that you stop treatment.

Ovarian Hyper-Stimulation Syndrome (OHSS)
If you are a woman, this medicine increases your risk of developing OHSS. This is when your follicles develop too much and become large cysts. If you get lower abdominal pain, gain any weight rapidly, feel sick or are vomiting or if you have difficulty in breathing, talk to your doctor straight away who might ask you to stop using this medicine (see section 4).
In case you are not ovulating, and if the recommended dose and schedule of administration are adhered to, the occurrence of OHSS is less likely. GONAL-f treatment seldom causes severeOHSS unless the medicine that is used for final follicular maturation (containing human Chorionic Gonadotropin , hCG) is administered. If you are developing OHSS your doctor may not give you any hCG in this treatment cycle and you may be told not to have sex or to use a barrier contraceptive method for at least four days.

Multiple pregnancy
When using GONAL-f, you have a higher risk of being pregnant with more than one child at the same time (?multiple pregnancy?, mostly twins), than if you conceived naturally. Multiple pregnancy may lead to medical complications for you and your babies. You can reduce the risk of multiple pregnancy by using the right dose of GONAL-f at the right times. When undergoing assisted reproductive technology the risk of having a multiple pregnancy is related your age, the quality and to the number of fertilised eggs or embryos placed inside you.

Miscarriage
When undergoing assisted reproductive technology or stimulation of your ovaries to produce eggs, you are more likely to have a miscarriage than the average woman.

Blood clotting problems (thromboembolic events)
If you had in the past or recently blood clots in the leg or in the lung, or a heart attack or stroke, or if those happened in your family, then you might have a higher risk that these problems occur or become worse with GONAL-f treatment.

Men with too much FSH in their blood
If you are a man, having too much FSH in your blood can be a sign of damaged testicles. GONAL-f usually does not work if you have this problem. If your doctor decides to try GONAL-f treatment, to monitor the treatment, they may ask you to provide semen for analysis 4 to 6 months after starting treatment.

Children
GONAL-f is not indicated for use in children.

Using other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

• If you use GONAL-f with other medicines which help ovulation (such as hCG or clomiphene citrate), this may increase the response of your follicles.
• If you use GONAL-f at the same time as a ?gonadotropin-releasing hormone? (GnRH) agonist or antagonist (these medicines reduce your sex hormone levels and stop you ovulating) you may need a higher dose of GONAL-f to produce follicles.

Pregnancy and breast-feeding

Do not use GONAL-f if you are pregnant or breast-feeding.

Driving and using machines

It is not expected that this medicine will affect your ability to drive and use machines.

Important information about some of the ingredients of GONAL-f

GONAL-f contains less than 1 mmol sodium (23 mg) per dose, therefore it is considered essentially ?sodium-free?.

Always use GONAL-fexactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Using this medicine

• GONAL-f is intended to be given by injection just under the skin (subcutaneously). The pre-filled pen can be used for several injections.
• The first injection of GONAL-f should be given under supervision of your doctor.
• Your doctor or nurse will show you how to use the GONAL-f pre-filled pen to inject the medicine.
• If you administer GONAL-f to yourself, please carefully read and follow the instructions at the end of this leaflet called ?How to use the GONAL-f pre-filled pen?.

How much to use

Your doctor will decide how much medicine you will take and how often. The doses described below are stated in International Units (IU) and millilitres (ml).

Women

If you are not ovulating and have irregular or no periods.

• GONAL-f is usually given every day.
• If you have irregular periods, start using GONAL-f within the first 7 days of your menstrual cycle. If you do not have periods you can start using the medicine on any convenient day.
• The usual starting dose of GONAL-f is 75 to 150 IU (0.12 to 0.24 ml) each day.
• Your dose of GONAL-f may be increased every 7 or every 14 days by 37.5 to 75 IU, until you get the desired response.
• The maximum daily dose of GONAL-f is usually not higher than 225 IU (0.36 ml).
• When you get the desired response, you will be given a single injection of 250 micrograms of ?recombinant hCG? (r-hCG, an hCG made in a laboratory by a special DNA technique), or 5,000 to 10,000 IU of hCG, 24 to 48 hours after your last GONAL-f injection. The best time to have sex is on the day of the hCG injection and the day after. If your doctor cannot see a desired response after 4 weeks, that treatment cycle with GONAL-f should be stopped. For the following treatment cycle, your doctor will give you a higher starting dose of GONAL-f than before.

If your body responds too strongly, your treatment will be stopped and you will not be given any hCG (see section 2, OHSS). For the following cycle, your doctor will give you a lower dose of GONAL-f than before.

If you are not ovulating, having no periods and have been diagnosed with very low levels of FSH and LH hormones

• The usual starting dose of GONAL-f is 75 to 150 IU (0.12 to 0.24 ml) together with 75 IU (0.12 ml) of lutropin alfa.
• You will use these two medicines each day for up to five weeks.
• Your dose of GONAL-f may be increased every 7 or every 14 days by 37.5 to 75 IU, until you get the desired response.
• When you get the desired response, you will be given a single injection of 250 micrograms of ?recombinant hCG? (r-hCG, an hCG made in a laboratory by a special DNA technique), or 5,000 to 10,000 IU of hCG, 24 to 48 hours after your last injections of GONAL-f and lutropin alfa. The best time to have sex is on the day of the hCG injection and the day after. Alternatively, intrauterine insemination may be performed by placing the sperm into the womb cavity. If your doctor cannot see a response after 5 weeks, that treatment cycle with GONAL-f should be stopped. For the following cycle, your doctor will give you a higher starting dose of GONAL-f than before. If your body responds too strongly, your treatment with GONAL-f will be stopped and you will not be given any hCG (see section 2, OHSS). For the following cycle, your doctor will give you a lower dose of GONAL-f than before.

If you need to develop several eggs for collection prior to any assisted reproductive technology

• The usual starting dose of GONAL-f is 150 to 225 IU (0.24 to 0.36 ml) each day, from day 2 or 3 of your treatment cycle.
• GONAL-f dose may be increased, depending on your response. The maximum daily dose is 450 IU (0.72 ml).
• Treatment is continued until your eggs have developed to a desired point. This usually takes about 10 days but can take any time between 5 and 20 days. Your doctor will use blood tests and/or an ultrasound machine to check when this is.
• When your eggs are ready, you will be given a single injection of 250 micrograms ?recombinant hCG? (r-hCG, an hCG made in a laboratory by a special recombinant DNA technique), or 5,000 IU to 10,000 IU of hCG, 24 to 48 hours after the last GONAL-f injection. This gets your eggs ready for collection. In other cases, your doctor may first stop you from ovulating by using a gonadotropin-releasing hormone (GnRH) agonist or antagonist. Then GONAL-f is started approximately two weeks after start of agonist treatment. The GONAL-f and GnRH agonist are then both given until your follicles develop as desired. For example, after two weeks of GnRH agonist treatment, 150 to 225 IU GONAL-f is administered for 7 days. The dose is then adjusted according to your ovarian response. When GnRH

or 6th day of GONAL-f treatment and continued until antagonist is used, it is administered from the 5thovulation induction.

Men

• The usual dose of GONAL-f is 150 IU (0.24 ml) ) together with hCG.
• You will use these two medicines three times a week for at least 4 months.
• If you have not responded to treatment after 4 months, your doctor may suggest that you continue using these two medicines for at least 18 months.

If you use more GONAL-f than you should

The effects of taking too much GONAL-f are unknown, Nevertheless one could expect Ovarian Hyper-Stimulation Syndrome (OHSS) to occur, which is described in section 4. However the OHSS will only occur if hCG is also administered (see section 2, OHSS).

If you forget to use GONAL-f

If you forget to use GONAL-f, do not take a double dose to make up for a forgotten dose. Please talk to your doctor as soon as you notice that you forgot a dose..

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

Like all medicines, GONAL-f can cause side effects, although not every body gets them.

The frequency of possible side effects listed below is defined using the following convention:

• very common (affects more than 1 user in 10)
• common (affects 1 to 10 users in 100)
• uncommon (affects 1 to 10 users in 1,000)
• rare (affects 1 to 10 users in 10,000)
• very rare (affects less than 1 user in 10,000)

Serious side effects in women

• Lower abdominal pain together with nausea or vomiting may be the symptoms of Ovarian Hyper-Stimulation Syndrome (OHSS). This may indicate that the ovaries over-reacted to the treatment and that large ovarian cysts developed (see also section 2 ?Take Special Care with GONAL-f?). This side effect is common.
• The OHSS may become severe with clearly enlarged ovaries, decreased urine production, weight gain, difficulty in breathing and/or possible fluid accumulation in your stomach or chest. This side effect is uncommon.
• Complications of OHSS such as twisting of ovaries or blood clotting may occur rarely.
• Serious blood clotting complications (thromboembolic events) independent of OHSS may be found very rarely. This could cause chest pain, breathlessness, stroke or heart attack (see also section 2 ?Take special care with GONAL-f?).

Serious side effects in men and women

• Allergic reactions such as rash, red skin, hives, swelling of your face with difficulty breathing can sometimes be serious. This side effect is very rare.

If you notice any of the above-listed side effects you should immediately contact your doctor who might ask you to stop using GONAL-f.

Other side effects in women

Very common:

• Sacs of fluid within the ovaries (ovarian cysts)
• Headache
• Local reactions at the injection site, such as pain, redness, bruising, swelling and/or irritation Common:
• Abdominal pain
• Feeling sick, vomiting, diarrhoea, abdominal cramps and bloating Very rare:
• Allergic reactions such as rash, red skin, hives, swelling of your face with difficulty breathing may occur. These reactions can sometimes be serious.
• Your asthma may get worse

Other side effects in men

Very common:

• Local reactions at the injection site, such as pain, redness, bruising, swelling and/or irritation Common:
• Swelling of the veins above and behind the testicles (a varicocele).
• Breast development, acne or weight gain. Very rare:
• Allergic reactions such as rash, red skin, hives, swelling of your face with difficulty in breathing may occur. These reactions can sometimes be serious.
• Your asthma may get worse.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Keep out of the reach and sight of children.

Do not use GONAL-f after the expiry date which is stated on the cartridge label or carton after EXP. The expiry date refers to the last day of that month.

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

Within its shelf life, the product may be stored at or below 25°C for up to 3 months without being refrigerated again and must be discarded if it has not been used after 3 months.

Store in the original package in order to protect from light.

Do not use GONAL-f if you notice any visible signs of deterioration, if the liquid contains particles or is not clear.

Please write on the GONAL-f pre-filled pen the day you first use it.

• Once opened, it may be stored for a maximum of 28 days outside of the fridge (at or below 25°C).
• Do not use any medicine left in your pre-filled pen after 28 days. At the end of the treatment any unused solution must be discarded.

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.

What GONAL-f contains

• The active substance is follitropin alfa.
• There are 600 IU (44 micrograms) of follitropin alfa in each millilitre of liquid Each pre-filled pen with multidose cartridge delivers 300 IU (to 22 micrograms) in 0.5 ml.
• The other ingredients are poloxamer 188, sucrose, methionine, sodium dihydrogen phosphate monohydrate, disodium phosphate dihydrate, m-cresol, concentrated phosphoric acid, sodium hydroxide and water for injections.

What GONAL-f looks like and contents of the pack

• GONAL-f is presented as a clear, colourless liquid for injection in a pre-filled pen.
• It is supplied in packs with 1 pre-filled pen and 5 disposable needles .

Marketing Authorisation Holder

Merck Serono Europe Limited, 56 Marsh Wall, London E14 9TP, United Kingdom.

Manufacturer

Merck Serono S.p.A., Via delle Magnolie 15, I-70026 Modugno (Bari), Italy.
For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

BelgiëBelgiqueBelgien MERCK NVSA Brusselsesteenweg 288 B-3090 Overijse TélTel 32-2-686 07 11 LuxembourgLuxemburg MERCK NVSA Brusselsesteenweg 288 B-3090 Overijse, BelgiqueBelgien TélTel 32-2-686 07 11

Magyarország Merck Kft. Bocskai út 134-146. H-1113 Budapest Tel 36-1-463-8100 . . 83 1582 Te 359 28075 111

eská republika Merck spol. s r.o Na Hebenech II. 171810 CZ-140 00 Praha 4 Tel. 420 272084211 Malta Cherubino Ltd Delf Building Sliema Road MT-GZR 06 Gzira Malta Tel 356-21-3432701234

Danmark E. Merck AB Strandvejen 102 B, 4th DK-2900 Hellerup Tlf 45 35253550 Nederland Merck BV Tupolevlaan 41-61 NL-1119 NW Schiphol-Rijk Tel 31-20-6582800

Deutschland Merck Serono GmbH Alsfelder Straße 17 D-64289 Darmstadt Tel 49-6151-6285-0 Norge Merck Serono Norge Luhrtoppen 2 N-1470 Lørenskog Tlf 47 67 90 35 90

Eesti Merck Serono OÜ Ahtri 12, EE-10151, Tallinn Tel 372 6116220 Österreich Merck GesmbH. Zimbagasse 5 A-1147 Wien Tel 43 1 57600-0

Polska Merck Sp. z o.o. Al. Jerozolimskie 178 PL-02-486 Warszawa Tel. 48 22 53 59 700 Merck A.E. 41-45, GR-151 23 T 30-210-61 65 100

Portugal Merck, s.a. Rua Alfredo da Silva, 3-C P-1300-040 Lisboa Tel 351-21-361 35 00 España Merck S.L. María de Molina, 40 E-28006 Madrid Línea de Información 900 200 400 Tel 34-91-745 44 00

România MERCK d.o.o., Dunajska cesta 119 SI-1000 Lubliana, Slovenia Tel 386 1 560 3 800 France Merck Serono s.a.s. 37, rue Saint-Romain F-69379 Lyon cedex 08 Tél. 33-4-72 78 25 25 Numéro vert 0 800 888 024

Slovenija MERCK d.o.o. Dunajska cesta 119 SI-1000 Ljubljana Tel 386 1 560 3 800 Ireland Merck Serono Ltd Bedfont Cross, Stanwell Road Feltham, Middlesex TW14 8NX United Kingdom Tel 44-20 8818 7200

Ísland Icepharma hf Lynghálsi 13 IS-110 Reykjavík Tel 354 540 8000 Slovenská republika Merck spol. s r.o. Tuhovská 3 SK-831 06 Bratislava Tel 421 2 49 267 111

Italia Merck Serono S.p.A. Via Casilina 125 I-00176 Roma Tel 39-06-70 38 41 SuomiFinland Merck Oy Pihatörmä 1 C FIN-02240 Espoo PuhTel 358-9-8678 700

Sverige E. Merck AB S-195 87 Stockholm Tel 46-8-562 445 00 . . 35, CY-2234 , . 357 22490305

Latvija Merck Serono SIA Duntes iela 23A LV-1005, Rga Tel 371 67152500 United Kingdom Merck Serono Ltd Bedfont Cross, Stanwell Road Feltham, Middlesex TW14 8NX- UK Tel 44-20 8818 7200

Lietuva

Merck Serono UAB
Savanoriu pr. 192,
LT-44151 Kaunas
Tel: +370 37320603

This leaflet was last approved in

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HOW TO USE THE GONAL-f PRE-FILLED PEN

• This section tells you how to use your pen.
• Before starting to use your pen, please read these instructions the whole way through first.
• Only use this pen for you ? do not let anyone else use it.
• The numbers on the black dose selection dial and the red dose control scale are measured in International Units or IU. Your doctor will have told you how many IU to inject each day.
• Give yourself the injection at the same time each day.

Before you start

1. Wash your hands

• It is important that your hands and the things you use to get your pen ready are as clean as possible.

2. Find a clean area

• A good place is a clean table or kitchen surface.

3. Get together everything you need and lay them out:

• 2 alcohol swabs
• the pre-filled pen
• a needle.

1. pen cap 9. dose arrow

2. outer needle cap 10. black dose selection dial (in IU FSH)

3. peel-off seal 11. red dose control scale

4. inner needle cap 12. grey marker of complete dose delivery

5. removable needle 13. injection button

6. threaded tip

7. liquid holder

8. plunger piston

Please note: The scale that can be seen through the liquid holder shows how much of the medicine is left in the pen. Do not use it to set the dose.

Getting a new pen ready for the first time

1. Take off the pen cap

2. Put on a needle

• Take a new needle ? only use the ?single-use? needles supplied for the GONAL-f pre-filled pen.
• Check that the peel-off seal on the outer needle cap is not damaged or loose. If it is damaged or loose, do not use the needle and get another. Throw away the unused needle with the outer needle cap still on, in your household rubbish.
• Pull off the peel-off seal.
• Hold the outer needle cap firmly.
• Press the threaded tip of the pen into the outer needle cap and twist it clockwise.
• Twist it until it is firmly fixed.

3. Getting the liquid in the pen ready for use (also called ?priming? the pen)

• Set the dose arrow to 37.5 using the black dose selection dial - look for the small dot.
• Pull out the injection button as far as it will go.
• Take off the outer needle cap.
• Then take off the inner needle cap and hold the pen with the needle pointing upwards.
• Tap the liquid holder gently with your finger.
• this lets any air bubbles rise up towards the needle.
• With the needle still pointing upwards, press the injection button fully.
• A drop of liquid will appear at the tip of the needle; this shows that your pen is ready for injection.
• This liquid at the needle tip is the ?over-fill? from the pen.
• If no liquid appears the first time, pull out the injection button as far as it will go and press the button again until a drop of liquid appears.

Setting the dose

1. Set the dose you need by turning the black dose dial in either direction

• Turn the dial until the arrow is pointing to the dose you need.
• The black dial lets you set the dose in steps of 37.5 IU.
• The smallest dose is 37.5 IU and the largest is 300 IU.
• Important: carefully check the dose dial before moving on to the next step. This is because the dose cannot be changed after you have pulled out the injection button.
• If you realise that you have set and loaded a wrong dose, do not inject it. Discard the wrong dose in the sink and set the dose again.

2. Once you have set your dose, load the dose by pulling the injection button out as far as it

will go

• Take care to pull the button straight and not to twist it out ? twisting it might change the dose which you have set.
• When the injection button is pulled out, the loaded dose is shown on the red dose control scale which appears. It is shown by the last mark (flat arrow).
• The example in the picture shows the injection button pulled out and a loaded dose of 150 IU. The grey marker can now be seen.
• Important: check the red dose control scale on the injection button to make sure that the full dose has been loaded.
• If the loaded dose is lower than the set dose, then there was not enough medicine left in your pen for this dose.
• If this happens, follow the instructions given at the bottom of this column in the second bullet point of the ?More information about the red dose control scale? section.
• If the same dose is required every time, then the dose arrow can be left pointing at the same position on the dose dial.

Injecting the dose

1. Choose the place to give the injection ? where your doctor or nurse has told you (e.g. tummy,

front of thigh). To minimise skin irritation, select a different injection site each day.

2. Clean the skin where the injection is going by wiping with an alcohol swab

3. Inject the dose as you were told by your doctor or nurse

• Put the needle into the skin and press the injection button as far as it will go.
• Check that the grey marker on the injection button is no longer visible.
• This confirms that the dose has been given.
• You must keep the needle in the skin with the injection button pressed down for at least 10 seconds.
• After 10 seconds, keep the injection button pressed down, and take the needle out of the skin.

After the injection

1. Taking off the needle

• Take off the needle after each injection.
• Hold the pen firmly by the liquid holder.
• Carefully put back the outer needle cap onto the needle.
• Then grip the outer needle cap and unscrew the needle ? do this by turning anti-clockwise.
• Throw away the used needle with outer needle cap on, in your household rubbish.
• Now put the pen cap back onto the pen.

2. Storing the pen

• First take off the needle and put back on the pen cap - as described above.
• Then store the pen in a safe place.
• It is best to put it back into its original package.
• When the pen is empty, throw it away in your household rubbish.

More information about the red dose control scale

• When the pen is nearly empty, there may not be enough left for your last dose from that pen. The red dose control scale on the injection button is for you to check whether there is enough for your last dose from the pen. ? It can only be pulled out as far as the mark (flat arrow) showing the amount of medicine left in the pen.
• If the loaded dose is not enough to complete your injection, you can do one of two things: ? Either inject the part dose ? what is left in the pen. If you do this, write down straight away how much you have injected. Then give the rest of your dose from a new pen. ? Or throw away the pen and inject the full dose using a new pen.