GONAL-f 300 IU/0.50 ml (22 micrograms/0.50 ml) powder andsolvent for solution for injection

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 severe OHSS 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 to your age, the quality and 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 prepared solution can be used for several injections. GONAL-f must be administered immediately after preparation.
• The first injection of GONAL-f should be given under supervision of your doctor.
• Your doctor or nurse will show you how to inject GONAL-f before you can inject yourself.
• If you administer GONAL-f to yourself, please carefully read and follow the instructions at the end of this leaflet called ?How to prepare and use the GONAL-f powder and solution?.

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 (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 vial label or carton after EXP. The expiry date refers to the last day of that month.

Prior to reconstitution, do not store above 25°C.

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.

Once the solution has been prepared, it may be stored for a maximum of 28 days.

• Please write on the GONAL-f vial the day you prepared the solution.
• Do not store above 25°C. Do not freeze.
• Store in the original container, in order to protect from light.
• Do not use any GONAL-f solution left in the vial 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.

GONAL-f 300 IU/0.50 ml (22 micrograms/0.50 ml) should not be mixed with other medicines in the same injection.
GONAL-f 300 IU/0.50 ml (22 micrograms/0.50 ml) preparation is not to be mixed with other GONAL-f containers within the same vial or syringe.

What GONAL-f contains

• The active substance is follitropin alfa.
• Each vial contains 450 IU of follitropin alfa.
• After reconstitution, there are 300 IU (22 micrograms) of follitropin alfa in 0.5 ml solution, that means there are 600 IU (44 micrograms) in each millilitre of solution.
• The other ingredients are sucrose, sodium dihydrogen phosphate monohydrate, disodium phosphate dihydrate, concentrated phosphoric acid and sodium hydroxide.
• The solvent contains water for injections.

What GONAL-f looks like and contents of the pack

• GONAL-f is presented as a powder and solvent which are used to prepare a solution for injection.
• The powder is a white pellet in a multidose glass vial.
• The solvent is a clear colourless liquid in a pre-filled syringe, each containing 0.75 ml.
• GONAL-f is supplied in packs of 1 vial of powder with 1 pre-filled syringe of solvent and 4 disposable syringes for administration graduated in International Units (IU FSH).

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

--------------------------------------------------------------------------------------------------

HOW TO PREPARE AND USE THE GONAL-f POWDER AND SOLVENT

• This section tells you how to prepare and use your GONAL-f powder and solvent.
• Before starting the preparation, please read these instructions the whole way through first.
• Give yourself the injection at the same time each day.

1. Wash your hands and find a clean area

• It is important that your hands and the items you use be as clean as possible.
• A good place is a clean table or kitchen surface.

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

• 2 alcohol swabs
• The pre-filled syringe containing the solvent (the clear liquid)
• The vial containing GONAL-f (the white powder)
• An empty syringe for injection (see illustration below)

3.Preparing the solution

• Remove the protective caps from the powder vial and from the pre-filled syringe.
• Take your pre-filled syringe, insert the needle into the powder vial and slowly inject all the solvent into the vial containing the powder.
• Remove the syringe from the vial and throw it away (put the protective cap to avoid injuries).
• This vial contains several doses of GONAL-f. You will have to keep it several days and only draw the prescribed dose every day.

4. Getting ready the syringe for injection

• Swirl gently the vial of GONAL-f prepared in step 3, do not shake. Check that the solution is clear and does not contain any particles.
• Take the syringe for injection and fill it with air by pulling the plunger to the correct dose in International Units (IU FSH).
• Insert the needle into the vial, turn the vial upside down and inject the air into the vial.
• Draw the prescribed dose of GONAL-f into the syringe for administration by pulling the plunger until it reaches the correct dose in IU FSH.

5. Removing air bubbles

• If you see air bubbles in the syringe, hold the syringe with the needle pointing upwards and gently flick the syringe until all the air collects at the top. Push the plunger until the air bubbles are gone.

6. Injecting the dose

• Immediately inject the solution: Your doctor or nurse will have already advised you where to inject (e.g. tummy, front of thigh). To minimise skin irritation, select a different injection site each day.
• Clean the chosen skin area with an alcohol swab using a circular motion.
• Firmly pinch the skin together and insert the needle at a 45° to 90° angle using a dart-like motion.
• Inject under the skin by pushing gently the plunger, as you were taught. Do not inject directly into a vein. Take as much time as you need to inject all the solution.
• Immediately withdraw the needle and clean the skin with an alcohol swab using a circular motion.

7. After the injection

• Once you have finished your injection, immediately discard the used syringes safely, preferably in a sharp container.
• Store the glass vial with the prepared solution in a safe place. You may need it again. The prepared solution is for your use alone and must not be given to other patients.
• For further injections with the prepared solution of GONAL-f, repeat steps 4. to 7.